TWI453204B - 1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase - Google Patents

1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase Download PDF

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TWI453204B
TWI453204B TW098122966A TW98122966A TWI453204B TW I453204 B TWI453204 B TW I453204B TW 098122966 A TW098122966 A TW 098122966A TW 98122966 A TW98122966 A TW 98122966A TW I453204 B TWI453204 B TW I453204B
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Andrew P Combs
Eddy W Yue
Richard B Sparks
Wenyu Zhu
Jiacheng Zhou
Qiyan Lin
Lingkai Weng
Tai-Yuen Yue
Pingli Liu
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Description

作為吲哚胺2,3-雙加氧酶抑制劑之1,2,5- 二唑1,2,5-oxadiazole as a guanamine 2,3-dioxygenase inhibitor

本發明係關於1,2,5-二唑衍生物，其為吲哚胺2,3-雙加氧酶之抑制劑且適用於治療癌症及其他病症，且係關於製備其之方法及中間物。The present invention relates to 1, 2, 5- An oxadiazole derivative which is an inhibitor of indoleamine 2,3-dioxygenase and which is useful in the treatment of cancer and other conditions, and is directed to methods and intermediates for preparing the same.

色胺酸(Trp)為生物合成蛋白質、菸鹼及神經傳遞素5-羥色胺(血清素)所需之必需胺基酸。酶吲哚胺2,3-雙加氧酶(亦稱作INDO或IDO)在L-色胺酸降解為N-甲醯基-犬尿胺酸中催化第一限制速率步驟。在人類細胞中，因IDO活性所致之Trp之消耗為重要的γ干擾素(IFN-γ)誘導抗微生物效應機制。IFN-γ刺激誘導IDO之活化，引起Trp消耗，藉此抑制Trp依賴性細胞內病原體(諸如弓蟲(Toxoplasma gondii )及砂眼披衣菌(Chlamydia trachomatis ))之生長。IDO活性亦對多種腫瘤細胞具有抗增殖作用，且已在活體內觀測到同種異體腫瘤之排斥反應期間之IDO誘導，表明此酶在腫瘤排斥反應過程中之可能作用(Daubener等人，1999,Adv.Exp.Med.Biol. ,467：517-24；Taylor等人，1991,FASEB J. ,5：2516-22)。Tryptophan (Trp) is an essential amino acid required for biosynthesis of proteins, nicotine and neurotransmitter serotonin (serotonin). The enzyme guanamine 2,3-dioxygenase (also known as INDO or IDO) catalyzes a first rate limiting step in the degradation of L-tryptophan to N-methyl thiol-kynurenic acid. In human cells, the consumption of Trp due to IDO activity is an important mechanism by which gamma interferon (IFN-γ) induces an antimicrobial effect. IFN-γ stimulation induces activation of IDO, causing Trp depletion, thereby inhibiting the growth of Trp-dependent intracellular pathogens such as Toxoplasma gondii and Chlamydia trachomatis . IDO activity also has antiproliferative effects on a variety of tumor cells, and IDO induction during rejection of allogeneic tumors has been observed in vivo, indicating a possible role for this enzyme in tumor rejection (Daubener et al., 1999, Adv .Exp. Med. Biol. , 467: 517-24; Taylor et al, 1991, FASEB J. , 5: 2516-22).

已觀測到與外周血液淋巴細胞(PBL)共培養之海拉細胞(HeLa cell)經由上調IDO活性而獲得免疫抑制性表型。咸信經介白素-2(IL2)治療後PBL增殖減緩係因腫瘤細胞回應PBL分泌IFNG而釋放IDO所致。藉由1-甲基-色胺酸(1MT)(特異性IDO抑制劑)治療來消除此作用。已提出腫瘤細胞中之IDO活性可用於削弱抗腫瘤反應(Logan等人，2002,Immunology ,105：478-87)。HeLa cells co-cultured with peripheral blood lymphocytes (PBL) have been observed to obtain an immunosuppressive phenotype by up-regulating IDO activity. The slowing down of PBL proliferation after the treatment of Xianxin Jingbai-2 (IL2) was caused by the release of IDO by tumor cells in response to PBL secreting IFNG. This effect was abolished by treatment with 1-methyl-tryptophan (1MT) (specific IDO inhibitor). It has been suggested that IDO activity in tumor cells can be used to attenuate anti-tumor responses (Logan et al, 2002, Immunology , 105: 478-87).

近來，Trp消耗之免疫調節作用已倍受關注。多個證據表明IDO涉及誘導免疫耐受性。對哺乳動物懷孕、腫瘤抗性、慢性感染及自體免疫疾病之研究已展示表現IDO之細胞可抑制T細胞反應且促進耐受性。在與細胞免疫活化相關之疾病及病症(諸如感染、惡性病、自體免疫疾病及AIDS)中以及在懷孕期間已觀測到Trp分解代謝加速。舉例而言，在自體免疫疾病中已觀測到IFN含量增加及尿Trp代謝物含量升高；已假定在自體免疫疾病中發生之全身性或局部Trp消耗可與此等疾病之退化及消瘦症狀相關。為支持此假定，在自關節炎關節之滑液中分離之細胞中觀測到高含量之IDO。在人類免疫缺乏病毒(HIV)患者中IFN亦升高且IFN含量增加與惡化預後相關。因此，提出HIV感染慢性誘導IDO，且藉由機會性感染進一步增強，且Trp之慢性損失啟動可造成AIDS患者之惡病質、癡呆及腹瀉及可能免疫抑制之機制(Brown等人，1991,Adv.Exp.Med.Biol. ,294：425-35)。為此，近來已展示在HIV小鼠模型中，IDO抑制可提高病毒特異性T細胞之含量且同時減少病毒性感染巨噬細胞之數目(Portula等人，2005,Blood ,106：2382-90)。Recently, the immunomodulatory effects of Trp consumption have received much attention. Multiple lines of evidence indicate that IDO is involved in inducing immune tolerance. Studies on mammalian pregnancy, tumor resistance, chronic infection, and autoimmune diseases have demonstrated that cells expressing IDO can inhibit T cell responses and promote tolerance. Acceleration of Trp catabolism has been observed in diseases and conditions associated with cellular immune activation, such as infections, malignant diseases, autoimmune diseases, and AIDS, as well as during pregnancy. For example, an increase in IFN levels and an increase in urinary Trp metabolite levels have been observed in autoimmune diseases; it has been postulated that systemic or localized Trp depletion in autoimmune diseases can be associated with degeneration and wasting of such diseases. Symptoms are related. To support this hypothesis, high levels of IDO were observed in cells isolated from synovial fluid of arthritic joints. IFN is also elevated in human immunodeficiency virus (HIV) patients and increased IFN levels are associated with worsening prognosis. Therefore, it is proposed that HIV infection chronically induces IDO, and is further enhanced by opportunistic infection, and the chronic loss of Trp initiates the mechanism of cachexia, dementia and diarrhea and possible immunosuppression in AIDS patients (Brown et al., 1991, Adv . Exp .Med. Biol. , 294: 425-35). To this end, it has recently been shown that in HIV mouse models, IDO inhibition increases the content of virus-specific T cells while reducing the number of virally infected macrophages (Portula et al, 2005, Blood , 106:2382-90). .

咸信IDO在防止子宮中胎兒排斥反應之免疫抑制過程中起作用。40多年前，曾觀測到在懷孕期間，遺傳上不相干之哺乳動物胚體均能存活，不管組織移植免疫學預測何種情形(Medawar,1953,Symp.Soc.Exp.Biol. 7：320-38)。母體與胎兒之解剖學分離及胎兒之抗原不成熟性不能完全解釋胎兒同種異體移植存活。近來已關注母體之免疫耐受性。因為IDO係由人類融合細胞滋養層表現且在正常懷孕期間全身色胺酸濃度降低，所以假定母親-胎兒介面處之IDO表現為防止胎兒同種異體移植物之免疫排斥反應所必需的。為檢驗此假定，使懷孕小鼠(懷有同源或異源胎兒)暴露於1MT，且觀測到T細胞誘導之所有異源胚體之快速排斥反應。因此，藉由分解代謝色胺酸，哺乳動物胚體似乎抑制T細胞活性且自衛防禦排斥反應，且在鼠科動物懷孕期間阻斷色胺酸分解代謝使母體T細胞引起胎兒同種異體移植物排斥反應(Munn等人，1998,Science, 281：1191-3)。Xianxin IDO plays a role in preventing immunosuppression of fetal rejection in the uterus. More than 40 years ago, mammalian embryos that were genetically incompatible during pregnancy were observed to survive, regardless of what is predicted by tissue transplantation immunology (Medawar, 1953, Symp. Soc. Exp. Biol. 7:320- 38). The anatomical separation of the mother and the fetus and the antigenic immatureness of the fetus do not fully explain the survival of the fetal allograft. The immune tolerance of the mother has recently been paid attention to. Since IDO is expressed by the human fusion cell trophoblast and the systemic tryptophan concentration is reduced during normal pregnancy, it is assumed that the IDO at the maternal-fetal interface is required to prevent immune rejection of fetal allografts. To test this hypothesis, pregnant mice (with homologous or heterologous fetuses) were exposed to 1MT, and rapid rejection of all heterologous embryoid bodies induced by T cells was observed. Thus, by catabolizing tryptophan, mammalian embryo bodies appear to inhibit T cell activity and defend against self-defense rejection, and block tryptophan catabolism during murine pregnancy, causing maternal T cells to cause fetal allograft rejection Reaction (Munn et al., 1998, Science, 281: 1191-3).

基於IDO降解色胺酸之腫瘤免疫抗性機制的另一證據來自於以下觀測：大多數人類腫瘤構成性表現IDO，且免疫原性小鼠腫瘤細胞表現IDO可防止預免疫小鼠之排斥反應。在此作用下，特異性T細胞不積聚於腫瘤部位且可在明顯中毒不存在下藉由IDO抑制劑對小鼠進行全身性治療來部分地恢復。因此，有人提出癌症患者之治療性疫苗接種之功效可藉由伴隨投與IDO抑制劑來改善(Uyttenhove等人，2003,Nature Med. ,9：1269-74)。亦已展示IDO抑制劑(1-MT)可與化學治療劑協同降低小鼠腫瘤生長，表明IDO抑制亦可增強習知細胞毒素療法之抗腫瘤活性(Muller等人，2005,Nature Med. ,11：312-9)。Another evidence based on the mechanism of IDO degradation of tryptophan's tumor immune resistance stems from the observation that most human tumors constitute constitutively IDO, and that immunogenic mouse tumor cells exhibit IDO to prevent rejection in pre-immune mice. Under this effect, specific T cells do not accumulate at the tumor site and can be partially restored by systemic treatment of the mice with IDO inhibitors in the absence of significant poisoning. Therefore, it has been suggested that the efficacy of therapeutic vaccination of cancer patients can be improved by concomitant administration of IDO inhibitors (Uyttenhove et al, 2003, Nature Med. , 9: 1269-74). IDO inhibitors (1-MT) have also been shown to synergize with chemotherapeutic agents to reduce tumor growth in mice, suggesting that IDO inhibition also enhances the antitumor activity of conventional cytotoxic therapies (Muller et al., 2005, Nature Med. , 11 :312-9).

一種造成對腫瘤無免疫反應性之機制可為由致耐受性宿主APC呈遞腫瘤抗原。亦已描述共表現CD123(IL3RA)及CCR6且抑制T細胞增殖之人類IDO表現抗原呈遞細胞(APC)之亞群。成熟與不成熟CD123陽性樹突狀細胞均抑制T細胞活性，且1MT阻斷此IDO抑制活性(Munn等人，2002,Science, 297：1867-70)。亦已證實小鼠腫瘤引流淋巴結(TDLN)含有構成性表現免疫抑制量之IDO之類漿細胞樹突狀細胞(pDC)之亞群。儘管在活體外僅包含0.5%之淋巴結細胞，但此等pDC有效抑制T細胞對由pDC自身所呈遞之抗原之反應，且亦以顯性方式抑制T細胞對由非抑制性APC所呈遞之第三方抗原之反應。在pDC群體中，功能性IDO介導之抑制活性大部分孤立於共表現B譜系標記CD19之新穎pDC亞群。因此，假定在TDLN中IDO介導之pDC抑制作用產生有效抑制宿主抗腫瘤T細胞反應之局部微環境(Munn等人，2004,J.Clin.Invest .,114(2)：280-90)。One mechanism that causes no immunoreactivity to tumors can be the presentation of tumor antigens by the tolerogenic host APC. Subgroups of human IDOs expressing antigen presenting cells (APCs) that co-express CD123 (IL3RA) and CCR6 and inhibit T cell proliferation have also been described. Both mature and immature CD123-positive dendritic cells inhibit T cell activity, and 1MT blocks this IDO inhibitory activity (Munn et al, 2002, Science, 297: 1867-70). Mouse tumor draining lymph nodes (TDLN) have also been shown to contain subpopulations of plasma cell dendritic cells (pDC) that constitute an immunosuppressive amount of IDO. Although only 0.5% of lymph node cells are contained in vitro, these pDCs effectively inhibit the response of T cells to antigens presented by pDC itself, and also inhibit T cells in a dominant manner for presentation by non-inhibitory APCs. The reaction of the tripartite antigen. In the pDC population, the functional IDO-mediated inhibitory activity is largely isolated from the novel pDC subpopulation that co-expresses the B lineage marker CD19. Thus, it is hypothesized that IDO-mediated pDC inhibition in TDLN produces a local microenvironment that effectively inhibits host anti-tumor T cell responses (Munn et al, 2004, J. Clin . Invest ., 114(2): 280-90).

IDO降解色胺酸、血清素及褪黑激素之吲哚部分，且引起神經活性及免疫調節性代謝物(統稱犬尿胺酸)之產生。樹突狀細胞(DC)所表現之IDO藉由局部消耗色胺酸且增加促凋亡犬尿胺酸可極大影響T細胞增殖及存活。DC中之IDO誘導可為調節性T細胞所驅動之缺失耐受性之常見機制。因為預期該等致耐受性反應可在多種生理病理性條件下進行，所以色胺酸代謝及犬尿胺酸產生可代表免疫系統與神經系統之間的關鍵介面(Grohmann等人，2003,Trends Immunol .,24：242-8)。在持久免疫活化之狀態下，游離血清Trp之利用性減小，且作為血清素產生減少之結果，亦會影響血清素激活功能(Wirleitner等人，2003,Curr.Med.Chem. ,10：1581-91)。IDO degrades the purines of tryptophan, serotonin and melatonin and causes the production of neuroactive and immunomodulatory metabolites (collectively known as kynurenine). The IDO exhibited by dendritic cells (DC) can greatly affect T cell proliferation and survival by locally consuming tryptophan and increasing pro-apoptotic kynurenine. IDO induction in DCs can be a common mechanism of tolerance tolerance driven by regulatory T cells. Since these tolerogenic responses are expected to occur under a variety of physiological and pathological conditions, tryptophan metabolism and kynurenine production may represent a key interface between the immune system and the nervous system (Grohmann et al., 2003, Trends). Immunol ., 24:242-8). In the state of perpetual immune activation, the availability of free serum Trp is reduced, and as a result of reduced serotonin production, serotonin activation is also affected (Wirleitner et al., 2003, Curr. Med. Chem. , 10:1581). -91).

有趣地是，已觀測到投與干擾素α誘發神經精神副作用，諸如抑鬱症狀及認知功能改變。直接影響血清素激活性神經傳遞會導致此等副作用。另外，因為IDO活化導致色胺酸(血清素(5-HT)之前驅物)含量降低，所以IDO可藉由降低中樞5-HT合成而在此等神經精神副作用中起作用。此外，諸如3-羥基-犬尿胺酸(3-OH-KYN)及喹啉酸(QUIN)之犬尿胺酸代謝物對腦功能有毒性作用。3-OH-KYN能夠藉由增加反應性氧物質(ROS)之產生而產生氧化壓力，且QUIN可產生對海馬趾N-甲基-D-天冬胺酸(NMDA)受體的過度刺激，導致細胞凋亡及海馬萎縮。由NMDA過度刺激引起之ROS過度產生與海馬萎縮均與抑鬱症相關(Wichers及Maes,2004,J.Psychiatry Neurosci. ,29：11-17)。因此，IDO活性可在抑鬱症中起作用。Interestingly, it has been observed that administration of interferon alpha induces neuropsychiatric side effects such as depressive symptoms and cognitive function changes. Direct effects on serotonin-activated neurotransmission can cause these side effects. In addition, since IDO activation results in a decrease in the content of tryptophan (serotonin (5-HT) precursor), IDO can play a role in these neuropsychiatric side effects by reducing central 5-HT synthesis. In addition, kynurenine metabolites such as 3-hydroxy-kynurenic acid (3-OH-KYN) and quinolinic acid (QUIN) are toxic to brain function. 3-OH-KYN can produce oxidative stress by increasing the production of reactive oxygen species (ROS), and QUIN can produce excessive stimulation of the hippocampal N-methyl-D-aspartate (NMDA) receptor. Causes apoptosis and hippocampal atrophy. Both ROS overproduction and hippocampal atrophy caused by NMDA over-stimulation are associated with depression (Wichers and Maes, 2004, J. Psychiatry Neurosci. , 29: 11-17). Therefore, IDO activity can play a role in depression.

正在開發IDO小分子抑制劑以治療或預防IDO相關性疾病，諸如上述彼等疾病。舉例而言，二唑及其他雜環IDO抑制劑報導於US 2006/0258719及US 2007/0185165中。PCT公開案WO 99/29310報導改變T細胞介導之免疫性之方法，其包含使用IDO抑制劑(諸如1-甲基-DL-色胺酸、對-(3-苯并呋喃基)-DL-丙胺酸、對-[3-苯并(b)噻吩基]-DL-丙胺酸及6-硝基-L-色胺酸)來改變色胺酸及色胺酸代謝物之局部細胞外濃度(Munn,1999)。製造用於增強或降低T細胞耐受性之抗原呈遞細胞的方法報導於WO 03/087347(亦以歐洲專利1501918公開)中(Munn,2003)。具有吲哚胺-2,3-雙加氧酶(IDO)抑制活性之化合物進一步報導於WO 2004/094409中；且美國專利申請公開案第2004/0234623號係關於藉由將吲哚胺-2,3-雙加氧酶抑制劑與其他治療形式組合投與來治療患有癌症或感染之個體的方法。IDO small molecule inhibitors are being developed to treat or prevent IDO related diseases, such as those described above. For example, Diazoles and other heterocyclic IDO inhibitors are reported in US 2006/0258719 and US 2007/0185165. PCT Publication WO 99/29310 reports a method for altering T cell-mediated immunity comprising the use of IDO inhibitors (such as 1-methyl-DL-tryptophan, p-(3-benzofuranyl)-DL -Alanine, p-[3-benzo(b)thienyl]-DL-alanine and 6-nitro-L-tryptophan) to alter the local extracellular concentration of tryptophan and tryptophan metabolites (Munn, 1999). Methods of making antigen presenting cells for enhancing or reducing T cell tolerance are reported in WO 03/087347 (also disclosed in European Patent No. 1501918) (Munn, 2003). Compounds having indoleamine-2,3-dioxygenase (IDO) inhibitory activity are further described in WO 2004/094409; and U.S. Patent Application Publication No. 2004/0234623 A method of administering a 3-dioxygenase inhibitor in combination with other therapeutic modalities to treat an individual having cancer or an infection.

根據指示IDO在免疫抑制、腫瘤抗性及/或排斥反應、慢性感染、HIV感染、AIDS(包括其表現形式，諸如惡病質、癡呆及腹瀉)、自體免疫疾病或病症(諸如類風濕性關節炎)及免疫耐受性及防止子宮內胎兒排斥反應中之作用的實驗資料，需要旨在藉由抑制IDO活性來抑制色胺酸降解之治療劑。當T細胞受懷孕、惡性病或病毒(諸如HIV)抑制時，IDO抑制劑可用於活化T細胞且因此增強T細胞活化。IDO之抑制亦可為針對患有神經或神經精神疾病或病症(諸如抑鬱症)之患者的重要治療策略。本文中之化合物、組合物及方法有助於滿足目前對於IDO調節劑之需求。According to the indication IDO in immunosuppression, tumor resistance and / or rejection, chronic infection, HIV infection, AIDS (including its manifestations, such as cachexia, dementia and diarrhea), autoimmune diseases or conditions (such as rheumatoid arthritis) And experimental data on the role of immune tolerance and prevention of fetal rejection in the uterus require a therapeutic agent intended to inhibit the degradation of tryptophan by inhibiting IDO activity. When T cells are inhibited by pregnancy, malignancy or by viruses such as HIV, IDO inhibitors can be used to activate T cells and thus enhance T cell activation. Inhibition of IDO can also be an important therapeutic strategy for patients with neurological or neuropsychiatric diseases or conditions, such as depression. The compounds, compositions, and methods herein help to meet current demand for IDO modulators.

本發明尤其提供式I之IDO抑制劑：In particular, the present invention provides IDO inhibitors of Formula I:

或其醫藥學上可接受之鹽，其中組成變數在本文中定義。 Or a pharmaceutically acceptable salt thereof, wherein the compositional variables are defined herein.

本發明進一步提供包含式I化合物及至少一種醫藥學上可接受之載劑的醫藥組合物。The invention further provides a pharmaceutical composition comprising a compound of formula I and at least one pharmaceutically acceptable carrier.

本發明進一步提供抑制吲哚胺2,3-雙加氧酶活性之方法，其包含使吲哚胺2,3-雙加氧酶(IDO)與式I化合物或其醫藥學上可接受之鹽接觸。The invention further provides a method of inhibiting guanamine 2,3-dioxygenase activity comprising administering a guanamine 2,3-dioxygenase (IDO) to a compound of formula I or a pharmaceutically acceptable salt thereof contact.

本發明進一步提供抑制患者之免疫抑制之方法，其包含向該患者投與有效量之式I化合物或其醫藥學上可接受之鹽。The invention further provides a method of inhibiting immunosuppression in a patient comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

本發明進一步提供治療患者之癌症、病毒感染、抑鬱症、神經退化性病症、創傷、年齡相關性白內障、器官移植排斥反應或自體免疫疾病之方法，其包含向該患者投與治療有效量之式I化合物或其醫藥學上可接受之鹽。The invention further provides a method of treating cancer, viral infection, depression, neurodegenerative disorder, trauma, age-related cataract, organ transplant rejection or autoimmune disease in a patient comprising administering to the patient a therapeutically effective amount A compound of formula I or a pharmaceutically acceptable salt thereof.

本發明進一步提供治療患者之黑素瘤之方法，其包含向該患者投與治療有效量之式I化合物或其醫藥學上可接受之鹽。The invention further provides a method of treating melanoma in a patient comprising administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

本發明進一步提供用於治療之式I化合物或其醫藥學上可接受之鹽。The invention further provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in therapy.

本發明進一步提供式I化合物或其醫藥學上可接受之鹽的用途，係用於製備供治療使用之藥物。The invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for therapeutic use.

本發明進一步提供中間物、其製備方法，及含有其之組合物，該等中間物適用於製備式F15化合物：The invention further provides an intermediate, a process for the preparation thereof, and a composition comprising the same, which are suitable for the preparation of a compound of formula F15:

本發明進一步提供中間物、其製備方法，及含有其之組合物，該等中間物適用於製備式F19化合物：The invention further provides an intermediate, a process for the preparation thereof, and a composition comprising the same, which are suitable for the preparation of a compound of formula F19:

本發明進一步提供中間物、其製備方法，及含有其之組合物，該等中間物適用於製備式F28化合物：The invention further provides an intermediate, a process for the preparation thereof, and a composition comprising the same, which are suitable for the preparation of a compound of formula F28:

本發明尤其提供式I之IDO抑制劑：In particular, the present invention provides IDO inhibitors of Formula I:

或其醫藥學上可接受之鹽，其中：R1 為NH2 或CH3 ；R2 為Cl、Br、CF3 、CH3 或CN；R3 為H或F；且n為1或2。 Or a pharmaceutically acceptable salt thereof, wherein: R 1 is NH 2 or CH 3 ; R 2 is Cl, Br, CF 3 , CH 3 or CN; R 3 is H or F; and n is 1 or 2.

在一些實施例中，R1 為NH2 。In some embodiments, R 1 is NH 2 .

在一些實施例中，R1 為CH3 。In some embodiments, R 1 is CH 3 .

在一些實施例中，R2 為Cl。In some embodiments, R 2 is Cl.

在一些實施例中，R2 為Br。In some embodiments, R 2 is Br.

在一些實施例中，R2 為CF3 。In some embodiments, R 2 is CF 3 .

在一些實施例中，R2 為CH3 。In some embodiments, R 2 is CH 3 .

在一些實施例中，R2 為CN。In some embodiments, R 2 is CN.

在一些實施例中，R3 為H。In some embodiments, R 3 is H.

在一些實施例中，R3 為F。In some embodiments, R 3 is F.

在一些實施例中，n為1。In some embodiments, n is one.

在一些實施例中，n為2。In some embodiments, n is 2.

本發明化合物可以多種固體形式存在。如本文所用，「固體形式」欲指藉由諸如熔點、溶解度、穩定性、結晶度、吸濕性、水含量、TGA特徵、DSC特徵、DVS特徵、XRPD特徵等一或多種特性表徵之固體。固體形式例如可為非晶形、結晶體或其混合物。The compounds of the invention may exist in a variety of solid forms. As used herein, "solid form" is intended to mean a solid characterized by one or more characteristics such as melting point, solubility, stability, crystallinity, hygroscopicity, water content, TGA characteristics, DSC characteristics, DVS characteristics, XRPD characteristics, and the like. The solid form can be, for example, amorphous, crystalline or a mixture thereof.

不同結晶固體形式通常具有不同晶格(例如單位晶胞)且一般因此具有不同物理特性。在一些狀況下，不同結晶固體形式具有不同水含量或溶劑含量。不同晶格可藉由固態表徵法(諸如X射線粉末繞射法(XRPD))鑑別。諸如差示掃描熱量測定(DSC)、熱解重量分析(TGA)、動態氣相吸附(DVS)及其類似方法之其他表徵法進一步有助於鑑別固體形式且有助於測定穩定性及溶劑/水含量。Different crystalline solid forms typically have different crystal lattices (e.g., unit cells) and generally have different physical properties. In some cases, different crystalline solid forms have different water or solvent contents. Different crystal lattices can be identified by solid state characterization such as X-ray powder diffraction (XRPD). Other characterizations such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor phase adsorption (DVS), and the like, further aid in the identification of solid forms and aid in determining stability and solvent/ Water content.

在一態樣中，本發明提供4-({2-[(胺基磺醯基)胺基]乙基}胺基)-N -(3-溴-4-氟苯基)-N' -羥基-1,2,5-二唑-3-甲醯亞胺醯胺之各種固體形式(參見實例1)。在一些實施例中，固體形式為結晶固體。在一些實施例中，固體形式實質上無水(例如，含有少於約1%水，少於約0.5%水，少於約1.5%水，少於約2%水)。在一些實施例中，固體形式由約162℃至約166℃之熔點或集中於約162℃至約166℃之DSC吸熱曲線表徵。在一些實施例中，固體形式由約164℃之熔點或集中於約164℃之DSC吸熱曲線表徵。在一些實施例中，固體形式具有實質上如圖2所示之DSC熱分析圖。在其他實施例中，固體形式具有至少一個、兩個或三個選自以2θ表示之約18.4°、約18.9°、約21.8°、約23.9°、約29.2°及約38.7°之XRPD峰。在其他實施例中，固體形式具有實質上如圖1所示之XRPD圖。In one aspect, the present invention provides 4 - ({2 - [(sulfo amino acyl) amino] ethyl} amino) - N - (3- bromo-4-fluorophenyl) - N '- Hydroxy-1,2,5- Various solid forms of oxazol-3-carboxamimidamide (see Example 1). In some embodiments, the solid form is a crystalline solid. In some embodiments, the solid form is substantially anhydrous (eg, contains less than about 1% water, less than about 0.5% water, less than about 1.5% water, less than about 2% water). In some embodiments, the solid form is characterized by a melting point of from about 162 ° C to about 166 ° C or a DSC endotherm curve centered at from about 162 ° C to about 166 ° C. In some embodiments, the solid form is characterized by a melting point of about 164 ° C or a DSC endotherm curve centered at about 164 ° C. In some embodiments, the solid form has a DSC thermogram substantially as shown in FIG. In other embodiments, the solid form has at least one, two or three XRPD peaks selected from the group consisting of about 18.4°, about 18.9°, about 21.8°, about 23.9°, about 29.2°, and about 38.7°, expressed in 2θ. In other embodiments, the solid form has an XRPD pattern substantially as shown in FIG.

本發明進一步提供包含4-({2-[(胺基磺醯基)胺基]乙基}胺基)-N -(3-溴-4-氟苯基)-N' -羥基-1,2,5-二唑-3-甲醯亞胺醯胺之固體形式的組合物(參見實例1)。組合物可包含至少約50重量%、至少約75重量%、至少約90重量%、至少約95重量%或至少約99重量%固體形式。組合物亦可含有醫藥學上可接受之賦形劑。在一些實施例中，固體形式實質上經純化。The present invention further provides a comprising 4 - ({2 - [(sulfo amino acyl) amino] ethyl} amino) - N - (3- bromo-4-fluorophenyl) - N '- hydroxy-1, 2,5- A composition of the solid form of oxazol-3-carboxamimidamide (see Example 1). The composition may comprise at least about 50% by weight, at least about 75% by weight, at least about 90% by weight, at least about 95% by weight, or at least about 99% by weight solid form. The composition may also contain a pharmaceutically acceptable excipient. In some embodiments, the solid form is substantially purified.

XRPD反射(峰)圖通常視為特定結晶形式之指紋圖譜。熟知XRPD峰之相對強度可視(尤其)樣本製備技術、晶體大小分布、所用之各種濾光片、樣本安置程序及所採用之特定儀器廣泛變化。在一些狀況下，視儀器類型或設定而定，可觀測到新峰或現有峰可能消失。如本文所用，術語「峰」係指具有最大峰高度/強度之至少約4%之相對高度/強度之反射。此外，儀器偏差及其他因素會影響2θ值。因此，峰賦值(peak assignment)(諸如本文報導之彼等值)可偏離正或負約0.2°(2θ)，且如在XRPD之背景下所用之術語「實質上」在本文中意欲涵蓋上述偏差。The XRPD reflection (peak) map is generally considered to be a fingerprint of a particular crystalline form. It is well known that the relative intensities of the XRPD peaks can vary widely (especially) in sample preparation techniques, crystal size distribution, the various filters used, the sample placement procedure, and the particular instrument employed. In some cases, depending on the instrument type or setting, new peaks or existing peaks may be observed to disappear. As used herein, the term "peak" refers to a reflection having a relative height/intensity of at least about 4% of the maximum peak height/intensity. In addition, instrument bias and other factors can affect the 2θ value. Thus, peak assignments (such as those reported herein) may deviate from positive or negative by about 0.2° (2θ), and the term "substantially" as used in the context of XRPD is intended to encompass the above deviations herein. .

同樣，與DSC、TGA或其他熱力實驗有關之溫度讀數可視儀器、特定設定、樣本製備等因素而定偏離約±3℃。因此，應理解本文中報導之具有「實質上」如任一圖中所示之DSC熱分析圖的結晶形式適應該偏差。Similarly, temperature readings associated with DSC, TGA, or other thermal experiments may deviate by approximately ±3 °C depending on factors such as instrumentation, specific settings, and sample preparation. Thus, it should be understood that the crystalline form reported herein as having "substantially" a DSC thermogram as shown in any of the figures accommodates this bias.

本發明化合物之取代基可以群或範圍揭示於本說明書之不同處。特別希望本發明包括該等群及範圍內之成員的所有個別次組合。Substituents of the compounds of the invention may be disclosed in groups or ranges to different points in the specification. It is specifically intended that the present invention include all individual sub-combinations of the members of the group and the scope.

希望本發明化合物具穩定性。如本文所用之「穩定性」係指穩固性足以經受住以有用純度自反應混合物中分離且較佳能夠調配為有效治療劑之化合物。It is desirable that the compounds of the invention be stable. As used herein, "stability" refers to a compound that is sufficiently robust to withstand isolation from a reaction mixture in useful purity and which is preferably formulated as an effective therapeutic.

另外應瞭解，為清晰起見而在不同實施例之上下文中所述之本發明某些特徵亦可在單個實施例中組合提供。相反，為簡單起見而在單個實施例之上下文中所述之本發明的不同特徵亦可分開或以任何合適次組合形式提供。In addition, it is to be understood that certain features of the invention may be Conversely, various features of the inventions which are described in the context of a single embodiment for the sake of simplicity may be provided separately or in any suitable sub-combination.

本發明化合物另外意欲包括所有可能的幾何異構體。描述本發明化合物之順式及反式幾何異構體且其可作為異構體之混合物或作為經分離之異構形式來分離。結構圖中以波狀線「」表示之鍵意欲表明此結構表示順式或反式異構體，或順式與反式異構體依任何比例之混合物。The compounds of the invention are additionally intended to include all possible geometric isomers. The cis and trans geometric isomers of the compounds of the invention are described and may be isolated as a mixture of isomers or as isolated isomeric forms. The wavy line in the structure diagram" The indicated bond is intended to indicate that the structure represents a cis or trans isomer, or a mixture of cis and trans isomers in any ratio.

本發明化合物亦包括互變異構形式。互變異構形式由單鍵與相鄰雙鍵之交換以及伴隨性質子遷移產生。The compounds of the invention also include tautomeric forms. The tautomeric form is produced by the exchange of a single bond with an adjacent double bond and the accompanying proton transfer.

本發明化合物亦可包括中間物或最終化合物中存在之原子的所有同位素。同位素包括具有相同原子數但不同質量數的彼等原子。舉例而言，氫之同位素包括氚及氘。The compounds of the invention may also include all isotopes of the atoms present in the intermediate or final compound. Isotopes include those atoms having the same number of atoms but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium.

在一些實施例中，本發明化合物及其鹽實質上經分離。「實質上經分離」意謂化合物至少部分地或實質上自其形成或偵測於其中之環境中分離。部分分離可包括(例如)富含本發明化合物的組合物。實質分離可包括含有至少約50重量%、至少約60重量%、至少約70重量%、至少約80重量%、至少約90重量%、至少約95重量%、至少約97重量%或至少約99重量%本發明化合物或其鹽的組合物。用於分離化合物及其鹽之方法為此項技術中之常規方法。In some embodiments, the compounds of the invention and salts thereof are substantially isolated. "Substantially separated" means that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Partial separation can include, for example, a composition enriched in a compound of the invention. Substantial separation can include at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99. % by weight of a composition of a compound of the invention or a salt thereof. The method for isolating the compound and its salt is a conventional method in the art.

本發明亦包括本文所述化合物之鹽。如本文中所用之「鹽」係指所揭示化合物之衍生物，其中藉由將現有酸或鹼部分轉化為其鹽形式對親體化合物進行改質。鹽之實例包括(但不限於)諸如胺之鹼性殘基的無機酸(諸如HCl、HBr、H2 SO4 )或有機酸(諸如乙酸、苯甲酸、三氟乙酸)鹽；諸如羧酸之酸性殘基的鹼金屬(諸如Li、Na、K、Mg、Ca)或有機(諸如三烷基銨)鹽；及其類似鹽。可藉由習知化學方法自含有鹼性或酸性部分之親體化合物合成本發明之鹽。一般而言，可藉由使此等化合物之游離酸或鹼形式與化學計量數之適當鹼或酸在水或有機溶劑或兩者之混合物中反應來製備該等鹽；一般而言，如***、乙酸乙酯、乙醇、異丙醇或乙腈(ACN)之非水性介質較佳。The invention also includes salts of the compounds described herein. As used herein, "salt" refers to a derivative of the disclosed compound wherein the parent compound is modified by converting the existing acid or base moiety to its salt form. Examples of salts include, but are not limited to, mineral acids such as HCl, HBr, H 2 SO 4 or organic acids such as acetic acid, benzoic acid, trifluoroacetic acid, such as basic residues of amines; An alkali metal (such as Li, Na, K, Mg, Ca) or an organic (such as a trialkylammonium) salt of an acidic residue; and the like. The salt of the present invention can be synthesized from a parent compound containing a basic or acidic moiety by a conventional chemical method. In general, such salts can be prepared by reacting the free acid or base forms of such compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or mixtures of the two; in general, such as diethyl ether A non-aqueous medium of ethyl acetate, ethanol, isopropanol or acetonitrile (ACN) is preferred.

本發明之「醫藥學上可接受之鹽」包括上述「鹽」之亞類，其為親體化合物與例如非毒性無機酸或有機酸所形成之習知非毒性鹽。合適鹽之清單見於Remington's Pharmaceutical Sciences ，第17版，Mack Publishing Company,Easton,Pa.,1985，第1418頁及Journal of Pharmaceutical Science ,66,2(1977)中，各文獻之全文以引用的方式併入本文中。如本文所用之「醫藥學上可接受」一詞係指在正確醫學判斷範疇內適合與人類及動物組織接觸使用而無過度毒性、刺激、過敏反應或其他問題或併發症、與合理益處/風險比相匹配之彼等化合物、材料、組合物及/或劑型。The "pharmaceutically acceptable salt" of the present invention includes a subclass of the above "salt" which is a conventional non-toxic salt formed by a parent compound and, for example, a non-toxic inorganic or organic acid. A list of suitable salts can be found in Remington's Pharmaceutical Sciences , 17th Edition, Mack Publishing Company, Easton, Pa., 1985, page 1418 and Journal of Pharmaceutical Science , 66, 2 (1977), the entire disclosure of each of which is incorporated by reference. Into this article. As used herein, the term "pharmaceutically acceptable" means suitable for use in contact with humans and animal tissues in the context of correct medical judgment without excessive toxicity, irritation, allergic reactions or other problems or complications, and reasonable benefits/risks. Compounds, materials, compositions and/or dosage forms that match the ratio.

合成方法resolve resolution

本發明化合物可以熟習有機合成技術者所知之多種方式製備。本發明化合物可使用如下所述之方法以及合成有機化學技術中已知之合成方法或如熟習此項技術者所瞭解之其變化形式來合成。The compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using methods as described below, as well as synthetic methods known in the art of synthetic organic chemistry or variations thereof as would be understood by those skilled in the art.

本發明化合物可使用以下通用方法及程序、由易獲得之起始物質製備。應瞭解，在指定典型或較佳製程條件(亦即反應溫度、時間、反應物莫耳比、溶劑、壓力等條件)的情況下，亦可使用其他製程條件，除非另外說明。最佳反應條件可隨所用特定反應物或溶劑而變，但熟習此項技術者可藉由常規優化程序來判定該等條件。The compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures. It should be understood that other process conditions may be used in the case of specifying typical or preferred process conditions (i.e., reaction temperature, time, reactant molar ratio, solvent, pressure, etc.) unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents employed, but those skilled in the art can determine such conditions by routine optimization procedures.

可藉由此項技術中已知的任何合適方法監測本文所述之製程。舉例而言，可藉由光譜方式(諸如核磁共振光譜法(例如1 H或13 C)、紅外光譜法或分光光度測定法(例如UV-可見光))或藉由層析法(諸如高效液相層析法(HPLC)或薄層層析法(TLC))監測產物形成。反應所得之化合物可藉由此項技術中已知的任何合適方法純化。舉例而言，經由合適吸附劑(例如矽膠、氧化鋁及其類似物)之層析法(中壓)；HPLC或製備型薄層層析法；蒸餾；昇華；濕磨或再結晶。The processes described herein can be monitored by any suitable method known in the art. For example, by means of spectroscopy (such as nuclear magnetic resonance spectroscopy (such as 1 H or 13 C), infrared spectroscopy or spectrophotometry (such as UV-visible light)) or by chromatography (such as high-performance liquid phase) Product formation was monitored by chromatography (HPLC) or thin layer chromatography (TLC). The compound obtained by the reaction can be purified by any suitable method known in the art. For example, chromatography (medium pressure) via a suitable adsorbent (eg, silicone, alumina, and the like); HPLC or preparative thin layer chromatography; distillation; sublimation; wet milling or recrystallization.

化合物製備可涉及各種化學基團的保護及去保護。熟習此項技術者可容易地判定保護及去保護之需要及適當保護基之選擇。保護基之化學特性可見於(例如)Wuts及Greene,Greene's Protective Groups in Organic Synthesis ，第4版，John Wiley & Sons：New York,2006中，該文獻之全文以引用的方式併入本文中。Compound preparation can involve the protection and deprotection of various chemical groups. Those skilled in the art can readily determine the need for protection and deprotection and the choice of appropriate protection groups. The chemical nature of the protecting groups can be found, for example, in Wuts and Greene, Greene's Protective Groups in Organic Synthesis , 4th Ed., John Wiley & Sons: New York, 2006, which is incorporated herein by reference in its entirety.

本文中所述之反應過程可在熟習有機合成技術者可容易選擇的合適溶劑中進行。合適溶劑與起始物質(反應物)、中間物或產物在反應進行的溫度(亦即溶劑冷凍溫度至溶劑沸騰溫度範圍內之溫度)下可實質上不反應。指定反應可在一種溶劑或一種以上溶劑之混合物中進行。視反應步驟而定，可選擇用於彼特定反應步驟之合適溶劑。適當溶劑包括水、烷烴(諸如戊烷、己烷、庚烷、環己烷等烷烴或其混合物)、芳族溶劑(諸如苯、甲苯、二甲苯等溶劑)、醇(諸如甲醇、乙醇、異丙醇等醇)、醚(諸如二烷基醚、甲基第三丁基醚(MTBE)、四氫呋喃(THF)、二烷等醚)、酯(諸如乙酸乙酯、乙酸丁酯等酯)、鹵化溶劑(諸如二氯甲烷(DCM)、三氯甲烷、二氯乙烷、四氯乙烷)、二甲基甲醯胺(DMF)、二甲亞碸(DMSO)、丙酮、乙腈(ACN)、六甲基磷醯胺(HMPA)及N-甲基吡咯啶酮(NMP)。該等溶劑可以其濕形式或無水形式使用。The reaction process described herein can be carried out in a suitable solvent which can be readily selected by those skilled in the art of organic synthesis. The suitable solvent and the starting material (reactant), intermediate or product may be substantially unreactive at the temperature at which the reaction is carried out (i.e., the temperature at which the solvent freezes to the boiling temperature of the solvent). The specified reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the reaction step, suitable solvents for the particular reaction step can be selected. Suitable solvents include water, alkanes (alkanes such as pentane, hexane, heptane, cyclohexane or mixtures thereof), aromatic solvents (such as benzene, toluene, xylene, etc.), alcohols (such as methanol, ethanol, iso). Alcohols such as propanol), ethers (such as dialkyl ethers, methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), two Ethers such as alkanes), esters (such as ethyl acetate, butyl acetate, etc.), halogenated solvents (such as dichloromethane (DCM), chloroform, dichloroethane, tetrachloroethane), dimethylformamidine Amine (DMF), dimethyl hydrazine (DMSO), acetone, acetonitrile (ACN), hexamethylphosphoniumamine (HMPA) and N-methylpyrrolidone (NMP). These solvents can be used in their wet or anhydrous form.

可藉由此項技術中已知的多種任何方法拆分化合物之外消旋混合物。實例方法包括使用作為具有光學活性之成鹽有機酸之「對掌性拆分酸」進行分步再結晶。用於分步再結晶方法之合適拆分劑為(例如)光學活性酸，諸如D及L形式之酒石酸、二乙醯基酒石酸、二苯甲醯基酒石酸、扁桃酸、蘋果酸、乳酸或各種光學活性之樟腦磺酸。外消旋混合物之拆分亦可藉由在填充有光學活性拆分劑(例如二硝基苯甲醯基苯基甘胺酸)之管柱上溶離來進行。熟習此項技術者可判定合適的溶離溶劑組成。The racemic mixture of the compounds can be resolved by any of a variety of methods known in the art. An example method involves the use of a stepwise recrystallization as a "palphatic resolving acid" as an optically active salt-forming organic acid. Suitable resolving agents for the stepwise recrystallization process are, for example, optically active acids such as tartaric acid in the form of D and L, diterpene tartaric acid, benzhydryl tartaric acid, mandelic acid, malic acid, lactic acid or various Optically active camphorsulfonic acid. Resolution of the racemic mixture can also be carried out by dissolving on a column packed with an optically active resolving agent such as dinitrobenzimidylglycolic acid. Those skilled in the art can determine the appropriate dissolved solvent composition.

本發明化合物可(例如)使用如下文所述之反應途徑及技術來製備。The compounds of the invention can be prepared, for example, using the reaction routes and techniques as described below.

本發明之方法及中間物適用於製備IDO抑制劑。流程1中描述製備本發明化合物F15之一般流程。The methods and intermediates of the invention are suitable for use in the preparation of IDO inhibitors. The general procedure for the preparation of the compound F15 of the present invention is described in Scheme 1.

現參看流程1，本發明提供如下製備式F15化合物或其鹽(其中R2 為Cl、Br、CF3 、CH3 或CN；R3 為H或F；且n為1或2)之方法：使式F13化合物或其鹽(其中Pg1 為胺基保護基)與胺基去保護劑反應(步驟M)產生式F14化合物或其鹽；且使式F14化合物與鹼反應(步驟N)產生式F15化合物。式F15化合物可使用諸如水、乙醇、MTBE或其組合之溶劑、藉由濕磨或再結晶法純化。Referring now to Scheme 1, the present invention provides a process for the preparation of a compound of formula F15 or a salt thereof wherein R 2 is Cl, Br, CF 3 , CH 3 or CN; R 3 is H or F; and n is 1 or 2: Reaction of a compound of formula F13 or a salt thereof (wherein Pg 1 is an amine protecting group) with an amine deprotecting agent (step M) to produce a compound of formula F14 or a salt thereof; and reacting a compound of formula F14 with a base (step N) F15 compound. The compound of formula F15 can be purified by wet milling or recrystallization using a solvent such as water, ethanol, MTBE or a combination thereof.

在一些實施例中，R2 為Br，R3 為F，且n為1。In some embodiments, R 2 is Br, R 3 is F, and n is 1.

在一些實施例中，R2 為Br，R3 為F，且n為2。In some embodiments, R 2 is Br, R 3 is F, and n is 2.

在一些實施例中，R2 為Cl，R3 為F，且n為1。In some embodiments, R 2 is Cl, R 3 is F, and n is 1.

在一些實施例中，R2 為Cl，R3 為F，且n為2。In some embodiments, R 2 is Cl, R 3 is F, and n is 2.

在一些實施例中，R2 為CF3 ，R3 為F，且n為1。In some embodiments, R 2 is CF 3 , R 3 is F, and n is 1.

在一些實施例中，R2 為CF3 ，R3 為F，且n為2。In some embodiments, R 2 is CF 3 , R 3 is F, and n is 2.

在一些實施例中，R2 為CF3 ，R3 為H，且n為1。In some embodiments, R 2 is CF 3 , R 3 is H, and n is 1.

在一些實施例中，R2 為CF3 ，R3 為H，且n為2。In some embodiments, R 2 is CF 3 , R 3 is H, and n is 2.

在一些實施例中，R2 為CN，R3 為F，且n為1。In some embodiments, R 2 is CN, R 3 is F, and n is 1.

胺基保護基在有機合成中常用於防止胺基的非所要反應，同時進行所要轉化反應。胺基保護基使得易共價連接至氮原子以及與氮原子選擇性***。熟習此項技術者已知各種胺基保護基，大致分類為烷氧羰基(諸如乙氧羰基、第三丁氧羰基(Boc)、苯甲氧羰基(Cbz)、9-茀基甲氧羰基(Fmoc)及其類似基團)、醯基(諸如乙醯基(Ac)、苯甲醯基(Bz)及其類似基團)、磺醯基(諸如甲烷磺醯基、三氟甲烷磺醯基及其類似基團)、芳基烷基(諸如苯甲基、二苯基甲基、三苯基甲基(三苯甲基)及其類似基團)、烯基烷基(諸如烯丙基、異戊二烯基及其類似基團)、二芳基亞甲基(諸如(C6 H5 )2 C=N及其類似基團)及矽烷基(諸如第三丁基二甲基矽烷基、三異丙基矽烷基及其類似基團)。胺基保護基之化學特性可見於Wuts及Greene,Greene's Protective Groups in Organic Synthesis ，第4版，第696-926頁，John Wiley & Sons：New York,2006中。在一些實施例中，Pg1 可為烷氧羰基(諸如第三丁氧羰基)。Amino protecting groups are commonly used in organic synthesis to prevent undesired reactions of amine groups while carrying out the desired conversion reaction. The amine protecting group allows for easy covalent attachment to the nitrogen atom and selective splitting with the nitrogen atom. Various amine protecting groups are known to those skilled in the art and are broadly classified as alkoxycarbonyl groups (such as ethoxycarbonyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl ( Fmoc) and the like), anthracenyl (such as ethyl acetyl (Ac), benzamidine (Bz) and the like), sulfonyl (such as methanesulfonyl, trifluoromethanesulfonyl) And similar groups), arylalkyl groups (such as benzyl, diphenylmethyl, triphenylmethyl (trityl) and the like), alkenylalkyl (such as allyl) , isoprenyl and the like, diarylmethylene (such as (C 6 H 5 ) 2 C=N and the like) and decyl (such as tert-butyldimethyl decane) Base, triisopropyldecylalkyl and the like). The chemical nature of the amine protecting groups can be found in Wuts and Greene, Greene's Protective Groups in Organic Synthesis , 4th Edition, pages 696-926, John Wiley & Sons: New York, 2006. In some embodiments, Pg 1 can be an alkoxycarbonyl group (such as a third butoxycarbonyl group).

上述胺基保護基可使用專用於上述各種基團但不影響化合物之其他所要部分的多種現有胺基去保護劑便利地加以移除。可例如藉由酸(諸如三氟乙酸、甲苯磺酸、鹽酸及其類似酸)、已知可產生酸之試劑組合物(例如乙醯氯與甲醇之混合物)或路易斯酸(Lewis acid)(例如BF3 ．Et2 O)處理來移除(例如水解)氮原子上之第三丁氧羰基。可例如藉由氫及催化劑(諸如鈀/碳)處理來移除(例如氫解)氮原子上之苯甲醯氧羰基。在一些實施例中，胺基保護劑可為三氟乙酸。在一些實施例中，胺基去保護劑含有三氟乙酸及>0.5體積%之水，例如>1.0體積%之水，>1.5體積%之水，>2.0體積%之水，約2體積%至約10體積%之水，約10體積%至約20體積%之水，或約20體積%至約50體積%之水。在一些實施例中，胺基去保護劑可為三氟乙酸與水約98：2體積比之混合物。在一些實施例中，胺基去保護劑可為視情況存於溶劑(諸如水、THF或二烷)中之鹽酸。在該等實施例中，鹽酸可以約4 N(例如約1 N、約2 N、約3 N、約5 N、約6 N、約7 N、約8 N、約9 N或約10 N)之濃度存在。在一些實施例中，去保護可在醇(諸如異丙醇)中進行。在一些實施例中，步驟M(流程1)可在約-10℃至約60℃(例如約-10℃至約0℃，約0℃至約25℃，約25℃至約45℃，或約45℃至約60℃)之溫度下進行。The above amine protecting groups can be conveniently removed using a variety of existing amine deprotecting agents that are specific to the various groups described above without affecting other desirable portions of the compound. For example, an acid (such as trifluoroacetic acid, toluenesulfonic acid, hydrochloric acid, and the like), a reagent composition known to produce an acid (for example, a mixture of ethyl chloride and methanol) or a Lewis acid (for example, BF 3 .Et 2 O) is treated to remove (eg, hydrolyze) the third butoxycarbonyl group on the nitrogen atom. The benzamidine oxycarbonyl group on the nitrogen atom can be removed (e.g., hydrogenolyzed) by treatment with hydrogen and a catalyst such as palladium on carbon. In some embodiments, the amine based protecting agent can be trifluoroacetic acid. In some embodiments, the amine deprotecting agent comprises trifluoroacetic acid and >0.5% by volume water, such as >1.0% by volume water, >1.5% by volume water, >2.0% by volume water, about 2% by volume to About 10% by volume of water, from about 10% by volume to about 20% by volume of water, or from about 20% by volume to about 50% by volume of water. In some embodiments, the amine deprotecting agent can be a mixture of trifluoroacetic acid and water in a volume ratio of about 98:2. In some embodiments, the amine deprotecting agent can be optionally present in a solvent such as water, THF or two Hydrochloric acid in alkane). In such embodiments, the hydrochloric acid may be about 4 N (eg, about 1 N, about 2 N, about 3 N, about 5 N, about 6 N, about 7 N, about 8 N, about 9 N, or about 10 N) The concentration exists. In some embodiments, deprotection can be carried out in an alcohol such as isopropanol. In some embodiments, step M (Scheme 1) can be from about -10 ° C to about 60 ° C (eg, from about -10 ° C to about 0 ° C, from about 0 ° C to about 25 ° C, from about 25 ° C to about 45 ° C, or It is carried out at a temperature of from about 45 ° C to about 60 ° C.

可使用鹼、視情況在溶劑中使F14中之二唑酮環轉化(例如水解)以展現F15中之醯胺肟(步驟N，流程1)。以二唑酮形式保護醯胺肟可用於防止羥基或整個醯胺肟的不利反應。鹼可為有機鹼，諸如非環狀胺(例如三乙胺、二異丙基乙胺(DIPEA)等胺)或環狀胺(例如吡咯啶、哌啶等胺)；或無機鹼，諸如鹼(例如，NaOH、LiOH、KOH、Mg(OH)2 等鹼)。鹼可以樹脂(諸如Amberlite及其類似物)形式獲得。在一些其他實施例中，鹼可以水溶液形式提供，諸如約2 N溶液(例如約0.5 N溶液、約1 N溶液、約1.5 N溶液、約2.5 N溶液、約3 N至約5 N溶液、約5 N至約10 N溶液)。在一些實施例中，鹼為鹼金屬氫氧化物(諸如氫氧化鈉)。在一些實施例中，鹼可為2 N NaOH水溶液。在一些實施例中，溶劑可為甲醇或四氫呋喃(THF)。在一些實施例中，步驟N(流程1)可在約-10℃至約60℃(例如約-10℃至約0℃，約0℃至約25℃，約25℃至約45℃或約45℃至約60℃)之溫度下進行。Alkali, as appropriate, in the solvent to make F14 The oxazolone ring is converted (e.g., hydrolyzed) to exhibit amidoxime in F15 (step N, Scheme 1). Take The oxazolone form protects the amidoxime and can be used to prevent adverse reactions of the hydroxyl group or the entire amidoxime. The base may be an organic base such as a non-cyclic amine such as an amine such as triethylamine or diisopropylethylamine (DIPEA) or a cyclic amine (such as an amine such as pyrrolidine or piperidine); or an inorganic base such as a base. (for example, a base such as NaOH, LiOH, KOH, Mg(OH) 2 ). Alkali can be a resin (such as Amberlite And its analogs are obtained in the form. In some other embodiments, the base can be provided as an aqueous solution, such as about 2 N solution (eg, about 0.5 N solution, about 1 N solution, about 1.5 N solution, about 2.5 N solution, about 3 N to about 5 N solution, about 5 N to about 10 N solution). In some embodiments, the base is an alkali metal hydroxide such as sodium hydroxide. In some embodiments, the base can be an aqueous 2 N NaOH solution. In some embodiments, the solvent can be methanol or tetrahydrofuran (THF). In some embodiments, step N (Scheme 1) can be from about -10 ° C to about 60 ° C (eg, from about -10 ° C to about 0 ° C, from about 0 ° C to about 25 ° C, from about 25 ° C to about 45 ° C or about It is carried out at a temperature of from 45 ° C to about 60 ° C.

在步驟L(流程1)中，式F13化合物可如下獲得：視情況在溶劑中以Pg1 -NH-磺醯氯處理式F12化合物或其鹽，隨後以有機鹼處理所得混合物以產生式F13化合物。此步驟L(流程1)係使用經保護之胺基磺醯氯(Pg1 -NH-SO2 Cl)將一級胺F12轉化為磺醯脲F13。可製備經保護胺基磺醯氯且立即用於與F12反應。保護基可選自此項技術中已知用於保護胺或磺醯胺之任何保護基(見上文)。在一些實施例中，Pg1 可為烷氧羰基(諸如第三丁氧羰基)。在該等實施例中，可藉由使醇(諸如乙醇、第三丁醇及其類似醇)與氯磺醯異氰酸酯(ClS(O)2 NCO)反應來獲得烷氧羰基NH-磺醯氯。用於此反應之適當溶劑包括(但不限於)鹵化溶劑，諸如二氯甲烷及其類似溶劑。有機鹼可為用於中和在一級胺(諸如F12)與經保護胺基磺醯氯反應期間所產生之HCl的任何鹼。有機鹼可包括非環狀三級胺，諸如三(C1-6 )烷基胺(例如三乙胺、二異丙基乙胺(DIPEA)及其類似物)；環狀三級胺(例如N-甲基哌啶、1,4-二氮雜雙環[2.2.2]辛烷(DABCO)及其類似物)。在一些實施例中，有機鹼可為三乙胺。在一些實施例中，此步驟可在約-10℃至約60℃(例如約-10℃至約0℃，約0℃至約25℃，約25℃至約45℃或約45℃至約60℃)之溫度下進行。In the step L (Scheme 1), the compound of the formula F13 can be obtained by treating the compound of the formula F12 or a salt thereof with Pg 1 -NH-sulfonium chloride in a solvent, followed by treating the resulting mixture with an organic base to give a compound of the formula F13. . This step L (Scheme 1) converts the primary amine F12 to the sulfonylurea F13 using protected amine sulfonium chloride (Pg 1 -NH-SO 2 Cl). Protected amine sulfonium chloride can be prepared and used immediately to react with F12. The protecting group can be selected from any of the protecting groups known in the art for protecting amines or sulfonamides (see above). In some embodiments, Pg 1 can be an alkoxycarbonyl group (such as a third butoxycarbonyl group). In such embodiments, the alkoxycarbonyl NH-sulfonium chloride can be obtained by reacting an alcohol such as ethanol, a third butanol, and the like with chlorosulfonium isocyanate (ClS(O) 2 NCO). Suitable solvents for this reaction include, but are not limited to, halogenated solvents such as dichloromethane and the like. The organic base can be any base used to neutralize the HCl produced during the reaction of the primary amine (such as F12) with the protected amine sulfonium chloride. The organic base may include an acyclic tertiary amine such as a tri(C 1-6 )alkylamine (for example, triethylamine, diisopropylethylamine (DIPEA) and the like); a cyclic tertiary amine (for example) N-methylpiperidine, 1,4-diazabicyclo [2.2.2] octane (DABCO) and its analogs). In some embodiments, the organic base can be triethylamine. In some embodiments, this step can range from about -10 ° C to about 60 ° C (eg, from about -10 ° C to about 0 ° C, from about 0 ° C to about 25 ° C, from about 25 ° C to about 45 ° C or from about 45 ° C to about It is carried out at a temperature of 60 ° C).

可藉由使用還原劑將有機化合物還原至較低氧化態。還原一般涉及添加氫原子或自基團移除氧原子。可藉由添加氫(元素氫形式或使用氫化物試劑(諸如NaBH4 、LiAlH4 及其類似物))、使用三苯膦或使用碘化鈉、氯三甲基矽烷與甲醇之組合將諸如F11之有機疊氮化物還原成諸如F12之胺(步驟K，流程1)。在一些實施例中，式F12化合物可藉由還原式F11化合物或其鹽獲得。在一些實施例中，可在碘化鈉、氯三甲基矽烷及甲醇存在下進行還原。在一些實施例中，碘化鈉與氯三甲基矽烷之莫耳比可為約1.0，例如約0.9，約0.95，約1.0，約1.05或約1.1。在一些實施例中，可將氯三甲基矽烷以存於甲醇中之溶液形式添加至F11、碘化鈉與甲醇之混合物中。在一些實施例中，可在約室溫(例如約10℃至約50℃、約15℃至約40℃、約20℃至約30℃或約25℃至約30℃)下進行步驟K(流程1)。The organic compound can be reduced to a lower oxidation state by using a reducing agent. Reduction generally involves the addition of a hydrogen atom or the removal of an oxygen atom from a group. Such as F11 can be added by adding hydrogen (in the form of elemental hydrogen or using a hydride reagent such as NaBH 4 , LiAlH 4 and the like), using triphenylphosphine or using a combination of sodium iodide, chlorotrimethylnonane and methanol. The organic azide is reduced to an amine such as F12 (step K, Scheme 1). In some embodiments, a compound of formula F12 can be obtained by reduction of a compound of formula F11 or a salt thereof. In some embodiments, the reduction can be carried out in the presence of sodium iodide, chlorotrimethylnonane, and methanol. In some embodiments, the molar ratio of sodium iodide to chlorotrimethylnonane can be about 1.0, such as about 0.9, about 0.95, about 1.0, about 1.05, or about 1.1. In some embodiments, chlorotrimethylnonane can be added to a mixture of F11, sodium iodide and methanol as a solution in methanol. In some embodiments, step K can be performed at about room temperature (eg, from about 10 ° C to about 50 ° C, from about 15 ° C to about 40 ° C, from about 20 ° C to about 30 ° C, or from about 25 ° C to about 30 ° C) Process 1).

在一些狀況下，如由HPLC或NMR光譜法及其類似方法測定，獲得實質上純形式之胺基化合物F12證明有困難。儘管不希望受理論約束，但咸信一些此等胺可能因對矽膠之高親和力增加或因純化期間之非所要降解而難以藉由矽膠層析法純化。在該等實施例中，現參看流程2，式F12化合物可如下純化：使式F12化合物與胺基保護劑反應，以產生式F12'化合物或其鹽，其中Pg2 N為經保護之胺。此保護(步驟K')之後，可純化式F12'化合物以產生經純化之式F12'化合物，及使經純化之式F12'化合物與胺基去保護劑反應(步驟K")以產生經純化之式F12化合物。熟習此項技術者已知胺基保護劑及胺基去保護劑，諸如Wuts及Greene(如上文)中者。在一些實施例中，胺基保護劑為二碳酸二第三丁酯(Boc2 O)。在該等實施例中，Pg2 N為第三丁氧羰基-NH。在該等實施例中，胺基去保護劑為能移除Boc保護基之試劑(見上文)。在該等實施例中，胺基去保護劑為酸(例如鹽酸、三氟乙酸及其類似酸)，視情況於溶劑(諸如水、THF或二烷)中。在一些實施例中，鹽酸可以約4 N(例如約1 N、約2 N、約3 N、約5 N、約6 N、約7 N、約8 N、約9 N或約10 N)之濃度存在。在一些實施例中，去保護可在醇(諸如異丙醇)中進行。在一些實施例中，步驟K'或K"可在約-10℃至約60℃(例如約-10℃至約0℃，約0℃至約25℃，約25℃至約45℃，或約45℃至約60℃)之溫度進行。適當純化方法為熟習此項技術者已知，可包括層析、結晶、昇華及其類似方法。在一些實施例中，可藉由矽膠層析法進行純化。化合物之純度一般藉由物理方法(諸如測量熔點(在固體狀況下)，獲得NMR光譜，或進行HPLC分離)測定。若熔點降低，若NMR光譜中非所要信號減少，或若HPLC跡線中外來峰移除，則化合物可稱為已經純化。在一些實施例中，化合物實質上經純化。In some cases, obtaining the substantially pure form of the amine compound F12 proved difficult by HPLC or NMR spectroscopy and the like. While not wishing to be bound by theory, it is believed that some of these amines may be difficult to purify by gel chromatography due to increased affinity for tannin or due to undesired degradation during purification. In such embodiments, now referring to Scheme 2, a compound of formula F12 can be purified by reacting a compound of formula F12 with an amine protecting agent to yield a compound of formula F12' or a salt thereof, wherein Pg 2 N is a protected amine. Following this protection (step K'), the compound of formula F12' can be purified to yield a purified compound of formula F12', and the purified compound of formula F12' is reacted with an amine deprotecting agent (step K") to yield purified Compounds of formula F12 are known to those skilled in the art and are known in the art as amine protecting agents and amine deprotecting agents such as Wuts and Greene (as above). In some embodiments, the amine protecting agent is dicarbonate second. Butyl ester (Boc 2 O). In these embodiments, Pg 2 N is a third butoxycarbonyl-NH. In these embodiments, the amine deprotecting agent is a reagent capable of removing the Boc protecting group (see Above). In these embodiments, the amine deprotecting agent is an acid (eg, hydrochloric acid, trifluoroacetic acid, and the like), optionally in a solvent such as water, THF or In the alkane). In some embodiments, the hydrochloric acid can be about 4 N (eg, about 1 N, about 2 N, about 3 N, about 5 N, about 6 N, about 7 N, about 8 N, about 9 N, or about 10 N). The concentration is present. In some embodiments, deprotection can be carried out in an alcohol such as isopropanol. In some embodiments, step K' or K" can be from about -10 ° C to about 60 ° C (eg, from about -10 ° C to about 0 ° C, from about 0 ° C to about 25 ° C, from about 25 ° C to about 45 ° C, or The temperature is carried out at a temperature of from about 45 ° C to about 60 ° C. Suitable purification methods are known to those skilled in the art and may include chromatography, crystallization, sublimation, and the like. In some embodiments, by gel chromatography Purification is carried out. The purity of the compound is generally determined by physical methods such as measuring the melting point (under solid conditions, obtaining NMR spectra, or by HPLC separation). If the melting point is lowered, if the desired signal is reduced in the NMR spectrum, or if the HPLC trace Compounds may be said to have been purified by removal of foreign peaks in the line. In some embodiments, the compounds are substantially purified.

在一些實施例中，式F11化合物(流程1)可如下獲得：以疊氮試劑處理式F10化合物或其鹽(其中L1 可選自烷基磺醯基(諸如甲烷磺醯基)、鹵烷基磺醯基(諸如三氟甲烷磺醯基)、芳基磺醯基(諸如甲苯磺醯基)及其類似基團)以產生式F11化合物(步驟J)。在一些實施例中，L1 為烷基磺醯基。疊氮試劑包括能產生親核性疊氮離子之任何試劑。疊氮試劑之實例包括鹼金屬疊氮化物(諸如疊氮化鈉、疊氮化鉀等物)。在一些可選實施例中，諸如疊氮化鈉之疊氮試劑可與碘化鈉組合使用。用於此轉化之適當試劑為極性溶劑，包括DMF、DMSO、NMP及其類似溶劑。在一些實施例中，步驟J可在DMF中進行。步驟J可在例如約40℃至約100℃、約50℃至約90℃或約60℃至約80℃之高溫下進行。在一些實施例中，步驟J可在約50℃下進行。在一些實施例中，步驟J可在約85℃下進行。In some embodiments, the compound of Formula F11 (Scheme 1) can be obtained by treating a compound of Formula F10 or a salt thereof (wherein L 1 can be selected from alkylsulfonyl (such as methanesulfonyl)), a halogenated alkane, with an azide reagent. A sulfonyl group (such as trifluoromethanesulfonyl), an arylsulfonyl group (such as toluenesulfonyl) and the like to produce a compound of formula F11 (step J). In some embodiments, L 1 is alkylsulfonyl. The azide reagent includes any reagent that produces a nucleophilic azide ion. Examples of the azide reagent include an alkali metal azide such as sodium azide, potassium azide or the like. In some alternative embodiments, an azide reagent such as sodium azide can be used in combination with sodium iodide. Suitable reagents for this transformation are polar solvents including DMF, DMSO, NMP and the like. In some embodiments, step J can be performed in the DMF. Step J can be carried out, for example, at a temperature of from about 40 ° C to about 100 ° C, from about 50 ° C to about 90 ° C, or from about 60 ° C to about 80 ° C. In some embodiments, step J can be performed at about 50 °C. In some embodiments, step J can be performed at about 85 °C.

可以流程3中所示之一系列步驟獲得式F10化合物或其鹽。中間物4-胺基-N '-羥基-1,2,5-二唑-3-甲醯亞胺醯胺F2之製備已描述於J.Heterocycl.Chem. (1965),2 ,253中，該文獻之全文以引用的方式併入本文中，且其向氯肟F3之轉化已描述於Synth.Commun. (1988),18 ,1427中，該文獻之全文以引用的方式併入本文中。可使胺(諸如包括含有經保護官能基之胺的一級胺或二級胺，例如乙胺、2-甲氧基乙胺或二甲胺)與氯肟F3視情況在溶劑(諸如乙酸乙酯)中偶合，隨後添加有機鹼(諸如三乙胺或DIPEA以使反應中產生之HCl驟冷)，以產生醯胺肟化合物F4。可視情況在溶劑(諸如水、乙醇、乙二醇及其類似溶劑)中藉由鹼(諸如KOH、NaOH、LiOH、Mg(OH)2 、Al(OH)3 及其類似鹼)處理F4且使反應混合物在高溫(例如約70℃、約80℃、約90℃、約100℃、約110℃、約120℃、約130℃、約140℃、約150℃、約160℃、約170℃、約180℃、約190℃或約200℃)下回流來實現諸如F4之化合物的重排，使環碳上之胺基與肟碳上之胺基互換，以產生化合物F5。可藉由向含有鹽酸(視情況包括乙酸)之水性酸性混合物中添加F5來使醯胺肟F5再活化為氯肟F6。在F5轉化為F6之此過程中，可將F5之酸性混合物加熱至約45℃，諸如約30℃、約40℃、約50℃或約60℃之溫度，以實現溶解。可向此溶液中添加氯化鈉，且接著在低於約0℃(諸如低於約-10℃、低於約-5℃、低於約5℃或低於約10℃)之溫度下用視情況可以水溶液形式提供之亞硝酸鹽試劑處理。亞硝酸鹽試劑為能夠提供亞硝酸根陰離子之試劑。亞硝酸鹽試劑包括鹼金屬亞硝酸鹽(例如亞硝酸鈉、亞硝酸鉀及其類似鹽)及包括有機陽離子之有機亞硝酸鹽(例如亞硝酸四乙基銨)。在一些實施例中，乙酸乙酯、THF或二烷可用作共溶劑。氯肟F6可與芳族胺(諸如苯胺)視情況在極性溶劑(諸如甲醇、水、乙醇及其類似溶劑)中、在高溫(諸如約50℃、約60℃、約70℃、約80℃、約90℃、約100℃、約110℃或約120℃)下、視情況在無機鹼(諸如KHCO3 、NaHCO3 )存在下偶合以產生芳基醯胺肟F7。在一些實施例中，無機鹼可以水溶液形式提供。在一些實施例中，可在高溫下向反應混合物中添加無機鹼。接著可在高溫(諸如約50℃、約60℃、約70℃、約80℃、約90℃或約100℃)下、使用存於溶劑(諸如乙酸乙酯、二烷、THF及其類似溶劑)中之1,1'-羰基二咪唑(CDI)將F7之醯胺肟官能基以二唑酮之形式加以保護。接著可使用熟習此項技術者已知之甲氧基去保護劑(諸如Wuts及Greene,Greene's Protective Groups in Organic Synthesis ，第4版，第24-30頁，John Wiley & Sons：New York,2006中之彼等甲氧基去保護劑)將F8之甲氧基轉化為F9中之羥基。舉例而言，將三溴化硼添加至F8視情況存於溶劑(諸如鹵化溶劑(例如DCM、三氯甲烷及其類似溶劑)或乙酸乙酯)中之冷(諸如約-78℃至約25℃，例如約-78℃至約10℃、約-78℃至約0℃、約-78℃至約-10℃、約0℃至約25℃或約0℃至約10℃)溶液中。隨後，F9中之第一羥基可如下以離去基L1 O-之形式加以活化(參見F10)：依序用視情況存於溶劑(諸如乙酸乙酯或DCM)中之L1 Cl及有機鹼(諸如三乙胺或DIPEA)處理，以移除所產生之HCl。L1 (例如)可選自烷基磺醯基(例如甲烷磺醯基)、鹵烷基磺醯基(例如三氟甲烷磺醯基)、芳基磺醯基(例如甲苯磺醯基)及其類似物。接著可以用於置換(諸如藉由SN 2機制)離去基L1 O之任何親核試劑處理化合物F10。The compound of formula F10 or a salt thereof can be obtained in a series of steps as shown in Scheme 3. Intermediate 4-amino- N '-hydroxy-1,2,5- The preparation of oxazol-3-carboxamimidamide F2 has been described in J. Heterocycl. Chem . (1965), 2 , 253, the entire disclosure of which is incorporated herein by reference The transformation of F3 has been described in Synth. Commun. (1988), 18 , 1427, the entire disclosure of which is incorporated herein by reference. An amine such as a primary or secondary amine comprising an amine containing a protected functional group, such as ethylamine, 2-methoxyethylamine or dimethylamine, and chloroquinone F3 may optionally be present in a solvent such as ethyl acetate. Coupling, followed by the addition of an organic base such as triethylamine or DIPEA to quench the HCl produced in the reaction to produce the amidoxime compound F4. The F4 may be treated with a base such as KOH, NaOH, LiOH, Mg(OH) 2 , Al(OH) 3 and the like in a solvent such as water, ethanol, ethylene glycol and the like, and optionally The reaction mixture is at elevated temperature (e.g., about 70 ° C, about 80 ° C, about 90 ° C, about 100 ° C, about 110 ° C, about 120 ° C, about 130 ° C, about 140 ° C, about 150 ° C, about 160 ° C, about 170 ° C, Reflowing at about 180 ° C, about 190 ° C or about 200 ° C) to effect rearrangement of a compound such as F4, swapping the amine groups on the ring carbon with the amine groups on the ruthenium carbon to produce compound F5. Amidoxime F5 can be reactivated to chloranil F6 by the addition of F5 to an aqueous acidic mixture containing hydrochloric acid, optionally including acetic acid. During the conversion of F5 to F6, the acidic mixture of F5 can be heated to a temperature of about 45 ° C, such as about 30 ° C, about 40 ° C, about 50 ° C or about 60 ° C to effect dissolution. Sodium chloride can be added to the solution and then used at temperatures below about 0 ° C (such as below about -10 ° C, below about -5 ° C, below about 5 ° C or below about 10 ° C) The nitrite reagent may be supplied as an aqueous solution, as the case may be. The nitrite reagent is a reagent capable of providing a nitrite anion. Nitrite reagents include alkali metal nitrites (such as sodium nitrite, potassium nitrite, and the like) and organic nitrites including organic cations (e.g., tetraethylammonium nitrite). In some embodiments, ethyl acetate, THF or two Alkanes can be used as cosolvents. Chlorofluorene F6 may be combined with an aromatic amine such as aniline in a polar solvent such as methanol, water, ethanol, and the like at elevated temperatures (such as about 50 ° C, about 60 ° C, about 70 ° C, about 80 ° C). At about 90 ° C, about 100 ° C, about 110 ° C or about 120 ° C), optionally in the presence of an inorganic base such as KHCO 3 , NaHCO 3 to produce aryl amidoxime F7. In some embodiments, the inorganic base can be provided as an aqueous solution. In some embodiments, an inorganic base can be added to the reaction mixture at elevated temperatures. It can then be used in a solvent (such as ethyl acetate, two) at elevated temperatures (such as about 50 ° C, about 60 ° C, about 70 ° C, about 80 ° C, about 90 ° C or about 100 ° C). 1,1'-carbonyldiimidazole (CDI) in alkane, THF and the like), the amidoxime functional group of F7 The form of oxazolone is protected. A methoxy deprotecting agent known to those skilled in the art can then be used (such as Wuts and Greene, Greene's Protective Groups in Organic Synthesis , 4th edition, pages 24-30, John Wiley & Sons: New York, 2006). These methoxy deprotecting agents convert the methoxy group of F8 to the hydroxyl group of F9. For example, boron tribromide is added to F8 as the case may be cold in a solvent such as a halogenated solvent (eg, DCM, chloroform, and the like) or ethyl acetate (such as from about -78 ° C to about 25). °C, for example, from about -78 ° C to about 10 ° C, from about -78 ° C to about 0 ° C, from about -78 ° C to about -10 ° C, from about 0 ° C to about 25 ° C or from about 0 ° C to about 10 ° C). Subsequently, the first hydroxyl group in F9 can be activated as follows in the form of a leaving group L 1 O- (see F10): sequentially using L 1 Cl and organic in a solvent such as ethyl acetate or DCM. A base such as triethylamine or DIPEA is treated to remove the HCl produced. L 1 may , for example, be selected from alkyl sulfonyl (eg, methanesulfonyl), haloalkylsulfonyl (eg, trifluoromethanesulfonyl), arylsulfonyl (eg, toluenesulfonyl), and Its analogues. Compound F10 can then be treated with any nucleophile that is displaced (such as by the S N 2 mechanism) leaving the group L 1 O.

或者，可藉由流程4中所述之一系列步驟獲得式F12化合物。Alternatively, the compound of formula F12 can be obtained by a series of steps as described in Scheme 4.

現參看流程4，在一些實施例中，式F12化合物可如下獲得：使式F24化合物或其鹽(其中Pg3 N為經保護胺(例如(C6 H5 )3 C-NH、(C6 H5 )2 C=N及其類似物))與胺基去保護劑反應以產生式F12化合物，。可藉由熟習此項技術中已知之特定胺保護基之去保護方法(諸如Wuts及Greene,Greene's Protective Groups in Organic Synthesis ，第4版，第696-926頁，John Wiley & Sons：New York,2006中之彼等方法)完成化合物F24之處理以用NH2 置換Pg3 N(步驟Q)。在一些實施例中，當Pg3 N為(C6 H5 )2 C=N時，去保護劑可為：酸，諸如有機酸(例如三氟乙酸、甲烷磺酸及其類似酸)或無機酸(例如鹽酸)；氫及鈀；或酸性羥基胺(NH2 OH)。在一些實施例中，當Pg3 N為(C6 H5 )3 C-NH時，去保護劑可包括有機酸(諸如三氟乙酸、甲烷磺酸及其類似酸)及視情況選用之有機矽烷；氫及鈀；或液氨中之鈉。有機矽烷為含有至少一個Si-H鍵且與矽連接之其餘基團為烷基、芳基或其組合之化合物。有機矽烷之實例包括三烷基矽烷(例如三(異丙基)矽烷)、三芳基矽烷(例如三苯基矽烷)或二苯基甲基矽烷。步驟Q可在約-10℃至約60℃(例如約-10℃至約0℃，約0℃至約25℃，約25℃至約45℃或約45℃至約60℃)之溫度下進行。Referring now to Scheme 4, in some embodiments, a compound of formula F12 can be obtained by formulating a compound of formula F24 or a salt thereof (wherein Pg 3 N is a protected amine (eg, (C 6 H 5 ) 3 C-NH, (C 6 H 5 ) 2 C=N and its analogs)) are reacted with an amine deprotecting agent to produce a compound of formula F12. Deprotection methods by known amine protecting groups known in the art (such as Wuts and Greene, Greene's Protective Groups in Organic Synthesis , 4th edition, pages 696-926, John Wiley & Sons: New York, 2006). The method of Compound B) completes the treatment of Compound F24 to replace Pg 3 N with NH 2 (Step Q). In some embodiments, when Pg 3 N is (C 6 H 5 ) 2 C=N, the deprotecting agent can be: an acid such as an organic acid (eg, trifluoroacetic acid, methanesulfonic acid, and the like) or inorganic An acid such as hydrochloric acid; hydrogen and palladium; or an acidic hydroxylamine (NH 2 OH). In some embodiments, when Pg 3 N is (C 6 H 5 ) 3 C-NH, the deprotecting agent can include organic acids (such as trifluoroacetic acid, methanesulfonic acid, and the like) and, optionally, organic Decane; hydrogen and palladium; or sodium in liquid ammonia. The organodecane is a compound containing at least one Si-H bond and the remaining group attached to the oxime is an alkyl group, an aryl group or a combination thereof. Examples of the organic decane include a trialkyl decane such as tris(isopropyl)decane, a triaryl decane such as triphenyl decane or diphenylmethyl decane. Step Q can be at a temperature of from about -10 ° C to about 60 ° C (eg, from about -10 ° C to about 0 ° C, from about 0 ° C to about 25 ° C, from about 25 ° C to about 45 ° C or from about 45 ° C to about 60 ° C) get on.

可藉由醇F25與經保護之一級胺F22在偶合試劑存在下進行三信反應(Mitsunobu reaction)(步驟P)來製備作為經保護之二級胺的化合物F24。偶合試劑可為三級膦(諸如三芳基膦(例如三苯膦)或三烷基膦(例如三丁基膦))與偶氮二羧酸二烷基酯之組合。偶氮二羧酸二烷基酯具有一般結構：ROOC-N=N-COOR，其中R可為烷基(例如偶氮二甲酸二異丙酯、偶氮二甲酸二乙酯或偶氮二甲酸二對氯苯甲酯)。儘管不希望受理論限制，但咸信胺經三氟乙醯基部分保護(諸如在F22中)防止副反應且改良二級胺F24之產率。諸如F25之醇的羥基可在偶合試劑存在下活化。胺親核試劑可置換經活化之羥基以形成二級胺。三信反應可在溶劑中進行，該溶劑諸如醚，例如THF、二烷、二烷基醚及其類似醚；鹵化溶劑，例如二氯甲烷、三氯甲烷及其類似溶劑；非極性溶劑，例如苯、甲苯及其類似溶劑；極性質子惰性溶劑，諸如DMF、HMPA及其類似溶劑之。在一些實施例中，式F24化合物可如下獲得：以式F25化合物或其鹽及偶合試劑處理式F22化合物或其鹽以產生式F24化合物。在一些實施例中，此步驟可在約-10℃至約60℃(例如約-10℃至約0℃，約0℃至約25℃，約25℃至約45℃或約45℃至約60℃)之溫度下進行。Compound F24 as a protected secondary amine can be prepared by conducting a Mitsunobu reaction (step P) with an alcohol F25 and a protected primary amine F22 in the presence of a coupling reagent. The coupling reagent can be a combination of a tertiary phosphine such as a triarylphosphine (e.g., triphenylphosphine) or a trialkylphosphine (e.g., tributylphosphine) and a dialkyl azodicarboxylate. The dialkyl azodicarboxylate has the general structure: ROOC-N=N-COOR, wherein R can be an alkyl group (e.g., diisopropyl azodicarboxylate, diethyl azodicarboxylate or azodicarboxylic acid). Di-p-chlorobenzyl ester). Although not wishing to be bound by theory, the salty amine is partially protected by a trifluoroethyl group (such as in F22) to prevent side reactions and to improve the yield of secondary amine F24. The hydroxyl group of the alcohol such as F25 can be activated in the presence of a coupling reagent. The amine nucleophile can displace the activated hydroxyl group to form a secondary amine. The three-way reaction can be carried out in a solvent such as an ether such as THF, two Alkanes, dialkyl ethers and the like; halogenated solvents such as dichloromethane, chloroform and the like; non-polar solvents such as benzene, toluene and the like; polar aprotic solvents such as DMF, HMPA And similar solvents. In some embodiments, a compound of formula F24 can be obtained by treating a compound of formula F22 or a salt thereof with a compound of formula F25, or a salt thereof, and a coupling reagent to produce a compound of formula F24. In some embodiments, this step can range from about -10 ° C to about 60 ° C (eg, from about -10 ° C to about 0 ° C, from about 0 ° C to about 25 ° C, from about 25 ° C to about 45 ° C or from about 45 ° C to about It is carried out at a temperature of 60 ° C).

可藉由兩步法(步驟G'及O)自化合物F21製備化合物F22。可在高溫(諸如約50℃，例如約60℃、約65℃、約70℃、約80℃或約90℃)下、用視情況存於溶劑(諸如乙酸乙酯或THF)中之1,1'-羰基二咪唑(CDI)處理化合物F21，以將化合物F21中之醯胺肟轉化為存在於化合物F26中之二唑酮。此等化合物F26又可在有機鹼(諸如吡啶、三乙胺、DIPEA及其類似鹼)存在下、用視情況存於溶劑(諸如DCM、THF、二烷或乙酸乙酯)中之三氟乙酸酐處理以產生化合物F22。在一些實施例中，式F22化合物可如下獲得：用羰基二咪唑(CDI)處理式F21化合物或其鹽以產生式F26化合物或其鹽且用三氟乙酸酐處理式F26化合物以產生式F22化合物。Compound F22 can be prepared from compound F21 by a two-step process (steps G' and O). 1 may be optionally present in a solvent such as ethyl acetate or THF at elevated temperatures, such as about 50 ° C, such as about 60 ° C, about 65 ° C, about 70 ° C, about 80 ° C, or about 90 ° C. Treatment of compound F21 with 1 '-carbonyldiimidazole (CDI) to convert amidoxime in compound F21 to be present in compound F26 Oxazolone. These compounds F26 can in turn be present in a solvent (such as DCM, THF, II) in the presence of an organic base such as pyridine, triethylamine, DIPEA and the like. Treatment with trifluoroacetic anhydride in alkane or ethyl acetate) affords compound F22. In some embodiments, a compound of formula F22 can be obtained by treating a compound of formula F21 or a salt thereof with carbonyldiimidazole (CDI) to produce a compound of formula F26 or a salt thereof and treating a compound of formula F26 with trifluoroacetic anhydride to yield a compound of formula F22. .

現參看流程5(步驟P')且基於上述三信反應，本發明之另一態樣提供製備式F8化合物或其鹽之方法，其中R2 、R3 及n如本文中所定義；該方法包括使式F22化合物或其鹽及式F25'化合物或其鹽與偶合試劑視情況在溶劑(諸如THF、二烷基醚或二氯甲烷)中反應以產生式F8化合物。在一些實施例中，此步驟可在約-10℃至約60℃(例如約-10℃至約0℃，約0℃至約25℃，約25℃至約45℃或約45℃至約60℃)之溫度下進行。Referring now to Scheme 5 (Step P') and based on the above-described three-signal reaction, another aspect of the present invention provides a process for the preparation of a compound of Formula F8 or a salt thereof, wherein R 2 , R 3 and n are as defined herein; The compound of formula F22 or a salt thereof and a compound of formula F25' or a salt thereof, and a coupling reagent are optionally reacted in a solvent such as THF, dialkyl ether or dichloromethane to yield a compound of formula F8. In some embodiments, this step can range from about -10 ° C to about 60 ° C (eg, from about -10 ° C to about 0 ° C, from about 0 ° C to about 25 ° C, from about 25 ° C to about 45 ° C or from about 45 ° C to about It is carried out at a temperature of 60 ° C).

流程6描述將磺醯胺基引入胺基化合物F12中之替代路線。在鹼(步驟R)(諸如可為雜環鹼(例如吡啶)或三烷基胺(例如三乙胺、DIPEA及其類似物)(其各自可視情況用作此轉化之溶劑)之有機鹼)存在下用磺醯胺處理F12可產生諸如F14之磺醯脲。此反應可在諸如約130℃(例如約100℃、約110℃、約120℃、約130℃或約140℃)之高溫下進行。使用微波照射施加此加熱可為有利。微波照射可在以單模方式操作之市售微波爐(例如，購自Biotage之Initiator)中進行。含有二唑酮環之化合物F14可在鹼存在下去保護(例如水解)生成所要醯胺肟F15(步驟N')。鹼可為有機鹼，諸如非環狀胺(例如三乙胺、二異丙基乙胺(DIPEA)等胺)或環狀胺(例如吡咯啶、哌啶等胺)；或無機鹼，諸如鹼(例如NaOH、LiOH、KOH、Mg(OH)2 等鹼)。鹼可以樹脂(諸如Amberlite及其類似物)形式獲得。在一些其他實施例中，鹼可以水溶液形式提供，諸如約2 N溶液(例如約0.5 N溶液、約1 N溶液、約1.5 N溶液、約2.5 N溶液、約3 N至約5 N溶液、約5 N至約10 N溶液)。在一些實施例中，鹼可為鹼金屬氫氧化物(諸如氫氧化鈉)。在一些實施例中，鹼可為2 N NaOH水溶液。在一些實施例中，溶劑可為甲醇或四氫呋喃(THF)。在一些實施例中，去保護可在約-10℃至約60℃(例如約-10℃至約0℃，約0℃至約25℃，約25℃至約45℃或約45℃至約60℃)之溫度下進行。因此，本發明之此態樣提供製備式F15化合物或其鹽之方法，其中R2 、R3 及n如本文中所定義；該方法包括使式F12化合物或其鹽與磺醯胺及有機鹼反應以產生式F14化合物或其鹽，且使式F14化合物或其鹽與鹼反應以產生式F15化合物。Scheme 6 describes an alternative route for introducing a sulfonamide group into the amine compound F12. In the base (step R) (such as an organic base which may be a heterocyclic base (such as pyridine) or a trialkylamine (such as triethylamine, DIPEA and the like), each of which may optionally be used as a solvent for this conversion) Treatment of F12 with sulfonamide in the presence of sulfonamide can produce sulfonium urea such as F14. This reaction can be carried out at an elevated temperature such as about 130 ° C (e.g., about 100 ° C, about 110 ° C, about 120 ° C, about 130 ° C, or about 140 ° C). It may be advantageous to apply this heating using microwave irradiation. Microwave irradiation can be carried out in a commercially available microwave oven (e.g., from Initiator from Biotage) operating in a single mode. contain The oxazolone ring compound F14 can be protected (e.g., hydrolyzed) in the presence of a base to form the desired amidoxime F15 (step N'). The base may be an organic base such as a non-cyclic amine such as an amine such as triethylamine or diisopropylethylamine (DIPEA) or a cyclic amine (such as an amine such as pyrrolidine or piperidine); or an inorganic base such as a base. (eg bases such as NaOH, LiOH, KOH, Mg(OH) 2 ). Alkali can be a resin (such as Amberlite And its analogs are obtained in the form. In some other embodiments, the base can be provided as an aqueous solution, such as about 2 N solution (eg, about 0.5 N solution, about 1 N solution, about 1.5 N solution, about 2.5 N solution, about 3 N to about 5 N solution, about 5 N to about 10 N solution). In some embodiments, the base can be an alkali metal hydroxide such as sodium hydroxide. In some embodiments, the base can be an aqueous 2 N NaOH solution. In some embodiments, the solvent can be methanol or tetrahydrofuran (THF). In some embodiments, the deprotection can be from about -10 ° C to about 60 ° C (eg, from about -10 ° C to about 0 ° C, from about 0 ° C to about 25 ° C, from about 25 ° C to about 45 ° C or from about 45 ° C to about It is carried out at a temperature of 60 ° C). Accordingly, this aspect of the invention provides a process for the preparation of a compound of formula F15 or a salt thereof, wherein R 2 , R 3 and n are as defined herein; the process comprises reacting a compound of formula F12 or a salt thereof with a sulfonamide and an organic base The reaction is carried out to produce a compound of the formula F14 or a salt thereof, and a compound of the formula F14 or a salt thereof is reacted with a base to give a compound of the formula F15.

本發明進一步提供式F9、F12及F14化合物或其鹽，其中R2 為Cl、Br、CF3 、CH3 或CN；R3 為H或F；且n為1或2。The present invention further provides a compound of the formula F9, F12 and F14 or a salt thereof, wherein R 2 is Cl, Br, CF 3 , CH 3 or CN; R 3 is H or F; and n is 1 or 2.

在一些實施例中，R2 為Br，R3 為F，且n為1。In some embodiments, R 2 is Br, R 3 is F, and n is 1.

在一些實施例中，R2 為Br，R3 為F，且n為2。In some embodiments, R 2 is Br, R 3 is F, and n is 2.

在一些實施例中，R2 為Cl，R3 為F，且n為1。In some embodiments, R 2 is Cl, R 3 is F, and n is 1.

在一些實施例中，R2 為Cl，R3 為F，且n為2。In some embodiments, R 2 is Cl, R 3 is F, and n is 2.

在一些實施例中，R2 為CF3 ，R3 為F，且n為1。In some embodiments, R 2 is CF 3 , R 3 is F, and n is 1.

在一些實施例中，R2 為CF3 ，R3 為F，且n為2。In some embodiments, R 2 is CF 3 , R 3 is F, and n is 2.

在一些實施例中，R2 為CF3 ，R3 為H，且n為1。In some embodiments, R 2 is CF 3 , R 3 is H, and n is 1.

在一些實施例中，R2 為CF3 ，R3 為H，且n為2。In some embodiments, R 2 is CF 3 , R 3 is H, and n is 2.

在一些實施例中，R2 為CH3 ，R3 為F，且n為1。In some embodiments, R 2 is CH 3 , R 3 is F, and n is 1.

在一些實施例中，R2 為CN，R3 為F，且n為1。In some embodiments, R 2 is CN, R 3 is F, and n is 1.

現參看流程7，化合物F19可如下自一級胺基化合物F12獲得：視情況在諸如乙酸乙酯、鹵化溶劑(例如二氯甲烷、三氯甲烷及其類似溶劑)或醚溶劑(THF、***、二烷及其類似溶劑)之溶劑中、在諸如三(C1-6 )烷基胺(例如三乙胺、DIPEA及其類似物)或吡啶之有機鹼(以移除所產生之HCl)存在下用甲烷磺醯氯處理(步驟S)以產生磺醯胺F20。可用其他烷基磺醯基(例如乙基磺醯基)、鹵烷基磺醯基(例如三氟甲烷磺醯基)、芳基磺醯基(例如甲苯磺醯基)及其類似基團置換甲烷磺醯基而不改變程序。在一些實施例中，此步驟可在約-10℃至約60℃(例如約-10℃至約0℃，約0℃至約25℃，約25℃至約45℃或約45℃至約60℃)之溫度下進行。含有二唑酮環之磺醯胺化合物F20可在鹼存在下去保護(例如水解)生成所要醯胺肟F19(步驟N")。鹼可為有機鹼，諸如非環狀胺(例如三乙胺、二異丙基乙胺(DIPEA)等胺)或環狀胺(例如吡咯啶、哌啶等胺)；或無機鹼，諸如鹼金屬氫氧化物或鹼土金屬氫氧化物(例如NaOH、LiOH、KOH、Mg(OH)2 等鹼)。鹼可以樹脂(諸如Amberlite及其類似物)形式獲得。在一些其他實施例中，鹼可以水溶液形式提供，諸如約2 N溶液(例如約0.5 N溶液、約1 N溶液、約1.5 N溶液、約2.5 N溶液、約3 N至約5 N溶液、約5 N至約10 N溶液)。在一些實施例中，鹼為鹼金屬氫氧化物(例如氫氧化鈉)。在一些實施例中，鹼可為2 N NaOH水溶液。在一些實施例中，溶劑可為甲醇或四氫呋喃(THF)。在一些實施例中，去保護可在約-10℃至約60℃(例如約-10℃至約0℃，約0℃至約25℃，約25℃至約45℃或約45℃至約60℃)之溫度下進行。因此，本發明之另一態樣提供製備式F19化合物或其鹽之方法，其中R2 、R3 及n如本文中所定義；該方法包括使式F12化合物或其鹽與甲烷磺醯氯在有機鹼存在下反應以產生式F20化合物或其鹽，且使式F20化合物或其鹽與鹼反應以產生式F19化合物。在一些實施例中，鹼可為鹼金屬氫氧化物，諸如氫氧化鈉(例如2 N NaOH)。Referring now to Scheme 7, compound F19 can be obtained from the primary amine compound F12 as follows: in the case of ethyl acetate, a halogenated solvent (e.g., dichloromethane, chloroform, and the like) or an ether solvent (THF, diethyl ether, In the presence of alkane and its like solvent, in the presence of an organic base such as tris(C 1-6 )alkylamine (eg triethylamine, DIPEA and its analogs) or pyridine (to remove the produced HCl) Treatment with methane sulfonium chloride (step S) to produce sulfonamide F20. It can be replaced by other alkylsulfonyl groups (such as ethylsulfonyl), haloalkylsulfonyl (such as trifluoromethanesulfonyl), arylsulfonyl (such as toluenesulfonyl) and the like. Methane sulfonyl group without changing the procedure. In some embodiments, this step can range from about -10 ° C to about 60 ° C (eg, from about -10 ° C to about 0 ° C, from about 0 ° C to about 25 ° C, from about 25 ° C to about 45 ° C or from about 45 ° C to about It is carried out at a temperature of 60 ° C). contain The oxazolidine compound F20 of the oxazolone ring can be protected (e.g., hydrolyzed) in the presence of a base to form the desired amidoxime F19 (step N"). The base can be an organic base such as a non-cyclic amine (e.g., triethylamine, An amine such as isopropylethylamine (DIPEA) or a cyclic amine (such as an amine such as pyrrolidine or piperidine); or an inorganic base such as an alkali metal hydroxide or an alkaline earth metal hydroxide (such as NaOH, LiOH, KOH, Alkali such as Mg(OH) 2 ). Alkali can be a resin (such as Amberlite) And its analogs are obtained in the form. In some other embodiments, the base can be provided as an aqueous solution, such as about 2 N solution (eg, about 0.5 N solution, about 1 N solution, about 1.5 N solution, about 2.5 N solution, about 3 N to about 5 N solution, about 5 N to about 10 N solution). In some embodiments, the base is an alkali metal hydroxide (eg, sodium hydroxide). In some embodiments, the base can be an aqueous 2 N NaOH solution. In some embodiments, the solvent can be methanol or tetrahydrofuran (THF). In some embodiments, the deprotection can be from about -10 ° C to about 60 ° C (eg, from about -10 ° C to about 0 ° C, from about 0 ° C to about 25 ° C, from about 25 ° C to about 45 ° C or from about 45 ° C to about It is carried out at a temperature of 60 ° C). Accordingly, another aspect of the invention provides a process for the preparation of a compound of formula F19 or a salt thereof, wherein R 2 , R 3 and n are as defined herein; the process comprises reacting a compound of formula F12 or a salt thereof with methanesulfonyl chloride The reaction is carried out in the presence of an organic base to give a compound of the formula F20 or a salt thereof, and the compound of the formula F20 or a salt thereof is reacted with a base to give a compound of the formula F19. In some embodiments, the base can be an alkali metal hydroxide such as sodium hydroxide (eg, 2 N NaOH).

芳基或烷基磺醯胺(例如甲烷磺醯胺F19)可藉由流程8中所示之一系列步驟獲得。諸如F40之經單保護之1,n-二胺(例如市售N-(胺基烷基)(第三丁氧基)羧醯胺)可在諸如三乙胺、吡啶、DIPEA及其類似物之有機鹼(以移除所產生之HCl)存在下、視情況在諸如乙酸乙酯、鹵化溶劑(例如二氯甲烷、三氯甲烷及其類似溶劑)或醚溶劑(THF、***、二烷及其類似溶劑)之溶劑中、用磺醯氯(諸如芳基磺醯氯或烷基磺醯氯(例如甲烷磺醯氯))處理以產生磺醯胺F41(步驟S')。經單保護1,n-二胺F40上之保護基可選自各種胺基保護基，且可適當選擇合適去保護條件(見上文)以產生胺F33(步驟M')。在一些實施例中，保護基可為烷氧羰基(諸如第三丁氧羰基Boc)。在該等實施例中，胺基去保護劑可為視情況存於溶劑(諸如二烷)中之酸(例如鹽酸或三氟乙酸)。An aryl or alkyl sulfonamide such as methanesulfonamide F19 can be obtained by a series of steps as shown in Scheme 8. Mono-protected 1, n-diamines such as F40 (e.g., commercially available N-(aminoalkyl)(t-butoxy)carboxamide) can be used in, for example, triethylamine, pyridine, DIPEA, and the like. In the presence of an organic base (to remove the produced HCl), as in the case of ethyl acetate, a halogenated solvent (such as dichloromethane, chloroform and the like) or an ether solvent (THF, diethyl ether, Treatment with a sulfonium chloride such as arylsulfonyl chloride or alkylsulfonium chloride (e.g., methanesulfonyl chloride) to give the sulfonamide F41 in a solvent of the alkane and its like (step S'). The protecting group on the mono-protected 1,n-diamine F40 can be selected from various amine protecting groups, and suitable deprotection conditions (see above) can be suitably selected to produce the amine F33 (step M'). In some embodiments, the protecting group can be an alkoxycarbonyl group (such as a third butoxycarbonyl Boc). In such embodiments, the amine deprotecting agent can be optionally present in a solvent (such as two An acid in an alkane such as hydrochloric acid or trifluoroacetic acid.

氯肟F3之製備已描述於Synth.Commun .(1988),18 ,1427中，該文獻之全文以引用的方式併入本文中。可使胺(諸如一級或二級胺，包括含有經保護之官能基之胺，例如乙胺、2-甲氧基乙胺或二甲胺或F33)與氯肟F3視情況在溶劑(諸如乙酸乙酯或乙醇)中偶合，隨後添加有機鹼(諸如三乙胺或DIPEA以使反應產生之HCl驟冷)，以產生醯胺肟化合物F16(步驟C')。在一些實施例中，此步驟可在約-10℃至約60℃(例如約-10℃至約0℃，約0℃至約25℃，約25℃至約45℃或約45℃至約60℃)之溫度下進行。可藉由視情況在溶劑(諸如，水、乙醇、乙二醇及其類似溶劑)中用鹼(諸如KOH、NaOH、LiOH、Mg(OH)2 、Al(OH)3 及其類似鹼)處理F16且使反應混合物在高溫(例如約70℃、約80℃、約90℃、約100℃、約110℃、約120℃、約130℃、約140℃、約150℃、約160℃、約170℃、約180℃、約190℃或約200℃)下回流來完成諸如F16之化合物的重排，以使環碳上之胺基與肟碳上之胺基互換，以產生諸如F17之化合物(步驟D')。可藉由將F17添加至含有鹽酸(視情況包括乙酸)之水性酸性混合物中來將醯胺肟F17以氯肟F18之形式再活化(步驟E')。在F17轉化為F18之此過程中，可將F17之酸性混合物加熱至約45℃(諸如約30℃、約40℃、約50℃或約60℃)之溫度以實現溶解。可向此溶液中添加氯化鈉，且在低於約0℃，諸如低於約-10℃、低於約-5℃、低於約5℃或低於約10℃之溫度下以視情況可以水溶液形式提供之亞硝酸鹽試劑處理。亞硝酸鹽試劑為能夠提供亞硝酸根陰離子之試劑。亞硝酸鹽試劑包括鹼金屬亞硝酸鹽(例如亞硝酸鈉、亞硝酸鉀及其類似鹽)及包括有機陽離子之有機亞硝酸鹽(例如亞硝酸四乙基銨)。在一些實施例中，乙酸乙酯、THF或二烷可用作共溶劑。視情況在極性溶劑(諸如甲醇、水、乙醇及其類似溶劑)中，在室溫下，用芳族胺(諸如苯胺F27)取代F18中之氯可產生甲烷磺醯胺F19(步驟F')。在一些實施例中，可採用諸如約10℃、約20℃、約30℃、約40℃或約50℃之溫度。此反應可視情況在可以水溶液形式提供之無機鹼(諸如KHCO3 、NaHCO3 )存在下進行。The preparation of proguanil F3 has been described in Synth . Commun . (1988), 18 , 1427, the entire disclosure of which is incorporated herein by reference. Amines such as primary or secondary amines, including amines containing protected functional groups such as ethylamine, 2-methoxyethylamine or dimethylamine or F33, and chloroquinone F3 may optionally be employed in a solvent such as acetic acid Coupling in ethyl ester or ethanol), followed by addition of an organic base such as triethylamine or DIPEA to quench the HCl produced by the reaction to produce the amidoxime compound F16 (step C'). In some embodiments, this step can range from about -10 ° C to about 60 ° C (eg, from about -10 ° C to about 0 ° C, from about 0 ° C to about 25 ° C, from about 25 ° C to about 45 ° C or from about 45 ° C to about It is carried out at a temperature of 60 ° C). It can be treated with a base such as KOH, NaOH, LiOH, Mg(OH) 2 , Al(OH) 3 and the like in a solvent such as water, ethanol, ethylene glycol or the like as appropriate. F16 and subjecting the reaction mixture to elevated temperatures (e.g., about 70 ° C, about 80 ° C, about 90 ° C, about 100 ° C, about 110 ° C, about 120 ° C, about 130 ° C, about 140 ° C, about 150 ° C, about 160 ° C, about Reflowing at 170 ° C, about 180 ° C, about 190 ° C or about 200 ° C to complete the rearrangement of a compound such as F16 to interchange the amine group on the ring carbon with the amine group on the ruthenium carbon to produce a compound such as F17 (Step D'). Amidoxime F17 can be reactivated in the form of chlorohydrazine F18 by addition of F17 to an aqueous acidic mixture containing hydrochloric acid, optionally including acetic acid (step E'). During the conversion of F17 to F18, the acidic mixture of F17 can be heated to a temperature of about 45 ° C (such as about 30 ° C, about 40 ° C, about 50 ° C or about 60 ° C) to effect dissolution. Sodium chloride can be added to the solution at temperatures below about 0 ° C, such as below about -10 ° C, below about -5 ° C, below about 5 ° C, or below about 10 ° C, as appropriate. It can be treated with a nitrite reagent provided in the form of an aqueous solution. The nitrite reagent is a reagent capable of providing a nitrite anion. Nitrite reagents include alkali metal nitrites (such as sodium nitrite, potassium nitrite, and the like) and organic nitrites including organic cations (e.g., tetraethylammonium nitrite). In some embodiments, ethyl acetate, THF or two Alkanes can be used as cosolvents. Substituting an aromatic amine (such as aniline F27) for the chlorine in F18 at a room temperature in a polar solvent such as methanol, water, ethanol, and the like to produce methanesulfonamide F19 (step F') . In some embodiments, temperatures such as about 10 ° C, about 20 ° C, about 30 ° C, about 40 ° C, or about 50 ° C can be employed. This reaction can be carried out in the presence of an inorganic base (such as KHCO 3 , NaHCO 3 ) which can be supplied in the form of an aqueous solution.

因此，在本發明之另一態樣中，提供製備式F19化合物或其鹽之方法，其中R2 、R3 及n如本文所定義；該方法包括使式F17化合物或其鹽與鹽酸視情況在溶劑(諸如二烷)中反應，隨後用視情況呈水溶液形式之亞硝酸鹽試劑(諸如亞硝酸鈉)處理，以產生式F18化合物或其鹽，且使式F18化合物與式F27化合物或其鹽反應以產生式F19化合物。Accordingly, in another aspect of the invention, there is provided a process for the preparation of a compound of formula F19, or a salt thereof, wherein R 2 , R 3 and n are as defined herein; the process comprising reacting a compound of formula F17 or a salt thereof with hydrochloric acid, as appropriate In solvent (such as two The reaction in alkane) is then treated with a nitrite reagent (such as sodium nitrite), optionally in the form of an aqueous solution, to yield a compound of formula F18 or a salt thereof, and a compound of formula F18 is reacted with a compound of formula F27 or a salt thereof to produce F19 compound.

在一些實施例中，式F17化合物可如下獲得：在足以使溶劑回流之溫度(諸如130℃)下，在溶劑(諸如乙二醇)中，用鹼(諸如氫氧化鉀)處理式F16化合物以產生式F17化合物。In some embodiments, a compound of formula F17 can be obtained by treating a compound of formula F16 with a base such as potassium hydroxide in a solvent such as ethylene glycol at a temperature sufficient to reflux the solvent, such as at 130 °C. A compound of formula F17 is produced.

本發明進一步提供式F18化合物或其鹽，其中n為1或2。在一些實施例中，n為1。在一些實施例中，n為2。The present invention further provides a compound of the formula F18 or a salt thereof, wherein n is 1 or 2. In some embodiments, n is one. In some embodiments, n is 2.

可如流程9中所述獲得化合物F28。可使氯肟F6(見上文，流程1)與雜環胺(諸如式F38化合物)視情況在極性溶劑(諸如甲醇、水、乙醇及其類似溶劑)中、在鹼(諸如無機鹼或有機鹼(例如Et3 N、吡啶或DIPEA))存在下偶合以產生芳基醯胺肟F36(步驟F")。在一些實施例中，F6轉化為F36可在諸如約10℃、約20℃、約30℃、約40℃、約50℃、約60℃或約90℃之溫度下進行。在一些實施例中，無機鹼可以水溶液形式提供。在一些實施例中，可在高溫下向反應混合物中添加無機鹼。接著可在高溫(諸如約50℃、約60℃、約70℃、約80℃、約90℃或約100℃)下、使用存於溶劑(諸如乙酸乙酯、二烷、THF及其類似溶劑)中之1,1'-羰基二咪唑(CDI)將F36之醯胺肟官能基以二唑酮之形式加以保護(步驟G")。接著可藉由熟習此項技術者已知的甲氧基去保護方法(諸如Wuts及Greene,Greene's Protective Groups in Organic Synthesis ，第4版，第24-30頁，John Wiley & Sons：New York,2006中之彼等方法)將F35之甲氧基轉化為F34中之羥基(步驟H')。舉例而言，將三溴化硼添加至F35視情況於諸如鹵化溶劑(例如DCM、氯仿及其類似溶劑)或乙酸乙酯之溶劑中之冷(諸如約-78℃至約25℃，例如約-78℃至約10℃、約-78℃至約0℃、約-78℃至約-10℃、約0℃至約25℃或約0℃至約10℃)溶液中。隨後F34中之第一羥基如下以離去基L1 O-之形式活化(參見步驟I'，F32)：依序用視情況存於溶劑(諸如乙酸乙酯或DCM)中之L1 Cl及有機鹼(諸如三乙胺或DIPEA)處理以移除所產生之HCl。在化合物F32中，L1 可選自烷基磺醯基(例如甲烷磺醯基)、鹵烷基磺醯基(例如三氟甲烷磺醯基)、芳基磺醯基(例如甲苯磺醯基)及其類似物。接著可用任何親核試劑處理化合物F32以便SN 2置換離去基L1 O。在一些實施例中，此步驟可在約-10℃至約60℃(例如約-10℃至約0℃，約0℃至約25℃，約25℃至約45℃或約45℃至約60℃)之溫度下進行。Compound F28 can be obtained as described in Scheme 9. It is possible to make proguanil F6 (see above, Scheme 1) and heterocyclic amines (such as the compound of formula F38) as appropriate in polar solvents such as methanol, water, ethanol and the like, in bases such as inorganic bases or organic a base (e.g., Et 3 N, pyridine or DIPEA)) in the presence of a coupling to produce aromatic group amidoxime F36 (step F "). in some embodiments, F6 is converted to F36 may be such as about 10 ℃, about 20 ℃, It is carried out at a temperature of about 30 ° C, about 40 ° C, about 50 ° C, about 60 ° C or about 90 ° C. In some embodiments, the inorganic base can be provided as an aqueous solution. In some embodiments, it can be directed to the reaction mixture at elevated temperatures. An inorganic base is added thereto, and then it can be used in a solvent (such as ethyl acetate, two at a high temperature (such as about 50 ° C, about 60 ° C, about 70 ° C, about 80 ° C, about 90 ° C or about 100 ° C)). 1,1'-carbonyldiimidazole (CDI) in alkane, THF and the like), the amidoxime functional group of F36 The form of the oxazolone is protected (step G"). It can then be subjected to methoxy deprotection methods known to those skilled in the art (such as Wuts and Greene, Greene's Protective Groups in Organic Synthesis , 4th edition, 24th Pages -30, John Wiley & Sons: New York, 2006, by the method of converting the methoxy group of F35 to the hydroxyl group of F34 (step H'). For example, adding boron tribromide to F35 The case is cooled in a solvent such as a halogenated solvent (for example, DCM, chloroform or the like) or ethyl acetate (such as from about -78 ° C to about 25 ° C, for example from about -78 ° C to about 10 ° C, from about -78 ° C to About 0 ° C, about -78 ° C to about -10 ° C, about 0 ° C to about 25 ° C or about 0 ° C to about 10 ° C) in the solution. Then the first hydroxyl group in F34 is as follows leaving the group L 1 O- Formal activation (see step I', F32): treatment with L 1 Cl and an organic base (such as triethylamine or DIPEA), optionally in a solvent such as ethyl acetate or DCM, to remove the resulting HCl. In compound F32, L 1 may be selected from alkylsulfonyl (eg, methanesulfonyl), haloalkylsulfonyl (eg, trifluoromethanesulfonyl), arylsulfonyl (eg, toluene) The thiol group and its analogs. The compound F32 can then be treated with any nucleophile to displace the leaving group L 1 O by S N 2 . In some embodiments, this step can range from about -10 ° C to about 60 ° C (eg, about It is carried out at a temperature of from -10 ° C to about 0 ° C, from about 0 ° C to about 25 ° C, from about 25 ° C to about 45 ° C or from about 45 ° C to about 60 ° C.

當親核試劑為疊氮離子時，F32提供F31(步驟J')。疊氮試劑包括能產生親核性疊氮離子之任何試劑。疊氮試劑之實例包括鹼金屬疊氮化物(諸如疊氮化鈉、疊氮化鉀)。在一些可選實施例中，諸如疊氮化鈉之疊氮試劑可與碘化鈉組合使用。用於此轉化之適當試劑為極性溶劑，包括DMF、DMSO、NMP及其類似溶劑。在一些實施例中，此步驟可在DMF中進行。在一些實施例中，此步驟可在例如約40℃至約100℃、約50℃至約90℃或約60℃至約80℃之高溫下進行。在一些實施例中，此步驟可在50℃下進行。在一些實施例中，此步驟可在85℃下進行。可藉由添加氫(呈元素氫形式；使用氫化物試劑(諸如NaBH4 、LiAlH4 及其類似物))；使用三苯膦；或使用碘化鈉、氯三甲基矽烷與甲醇之組合將諸如F31之有機疊氮化物還原成諸如F29之有機胺(步驟K"')。在一些實施例中，可在碘化鈉、氯三甲基矽烷及甲醇存在下進行還原。在一些實施例中，還原可在約室溫(例如約10℃至約50℃，約15℃至約40℃，約20℃至約30℃或約25℃至約30℃)下進行。在一些實施例中，碘化鈉與氯三甲基矽烷之莫耳比可為約1.0，例如約0.9，約0.95，約1.0，約1.05或約1.1。在一些實施例中，可將氯三甲基矽烷以甲醇中之溶液形式添加至F31、碘化鈉與甲醇之混合物中。When the nucleophile is an azide ion, F32 provides F31 (step J'). The azide reagent includes any reagent that produces a nucleophilic azide ion. Examples of azide reagents include alkali metal azides (such as sodium azide, potassium azide). In some alternative embodiments, an azide reagent such as sodium azide can be used in combination with sodium iodide. Suitable reagents for this transformation are polar solvents including DMF, DMSO, NMP and the like. In some embodiments, this step can be performed in DMF. In some embodiments, this step can be carried out, for example, at a temperature of from about 40 ° C to about 100 ° C, from about 50 ° C to about 90 ° C, or from about 60 ° C to about 80 ° C. In some embodiments, this step can be performed at 50 °C. In some embodiments, this step can be performed at 85 °C. By adding hydrogen (in the form of elemental hydrogen; using a hydride reagent such as NaBH 4 , LiAlH 4 and its analogs); using triphenylphosphine; or using a combination of sodium iodide, chlorotrimethylnonane and methanol Reduction of the organic azide such as F31 to an organic amine such as F29 (step K"'). In some embodiments, the reduction can be carried out in the presence of sodium iodide, chlorotrimethylnonane, and methanol. In some embodiments The reduction can be carried out at about room temperature (e.g., from about 10 ° C to about 50 ° C, from about 15 ° C to about 40 ° C, from about 20 ° C to about 30 ° C or from about 25 ° C to about 30 ° C). In some embodiments, The molar ratio of sodium iodide to chlorotrimethylnonane can be about 1.0, such as about 0.9, about 0.95, about 1.0, about 1.05 or about 1.1. In some embodiments, chlorotrimethylnonane can be used in methanol. The solution is added to a mixture of F31, sodium iodide and methanol.

在鹼(諸如有機鹼，其可為雜環鹼(例如吡啶)或三烷基胺(例如三乙胺、DIPEA及其類似物)，其各自可視情況用作此轉化之溶劑)存在下用磺醯胺處理F29產生諸如F30之磺醯脲(步驟R')。此反應可在諸如約130℃(例如約100℃、約110℃、約120℃、約130℃或約140℃)之高溫下進行。使用微波照射施加此加熱可為有利。微波照射可在以單模方式操作之市售微波爐(例如購自Biotage之Initiator)中進行。含有二唑酮環之化合物F30可在鹼存在下去保護(例如水解)生成所要醯胺肟F28(步驟N"')。鹼可為有機鹼，諸如非環狀胺(例如三乙胺、二異丙基乙胺(DIPEA)等胺)或環狀胺(例如吡咯啶、哌啶等胺)；或無機鹼，諸如鹼(例如NaOH、LiOH、KOH、Mg(OH)2 等鹼)。鹼可以樹脂(諸如Amberlite及其類似物)形式獲得。在一些其他實施例中，鹼可以水溶液形式(水性鹼)提供，諸如約2 N溶液(例如約0.5 N溶液、約1 N溶液、約1.5 N溶液、約2.5 N溶液、約3 N至約5 N溶液、約5 N至約10 N溶液)。在一些實施例中，鹼可為鹼金屬氫氧化物(例如氫氧化鈉)。在一些實施例中，鹼可為2 N NaOH水溶液。在一些實施例中，溶劑可為甲醇或四氫呋喃(THF)。在一些實施例中，去保護可在約-10℃至約60℃(例如約-10℃至約0℃，約0℃至約25℃，約25℃至約45℃或約45℃至約60℃)之溫度下進行。In the presence of a base such as an organic base, which may be a heterocyclic base such as pyridine or a trialkylamine such as triethylamine, DIPEA and the like, each of which may optionally be used as a solvent for this conversion. Indoleamine treatment F29 produces a sulfonium urea such as F30 (step R'). This reaction can be carried out at an elevated temperature such as about 130 ° C (e.g., about 100 ° C, about 110 ° C, about 120 ° C, about 130 ° C, or about 140 ° C). It may be advantageous to apply this heating using microwave irradiation. Microwave irradiation can be carried out in a commercially available microwave oven (e.g., the Initiator available from Biotage) operating in a single mode. contain The oxazolone ring compound F30 can be protected (e.g., hydrolyzed) in the presence of a base to form the desired amidoxime F28 (step N"'). The base can be an organic base such as a non-cyclic amine (e.g., triethylamine, diisopropyl) An amine such as diethylamine (DIPEA) or a cyclic amine (such as an amine such as pyrrolidine or piperidine); or an inorganic base such as a base (such as a base such as NaOH, LiOH, KOH or Mg(OH) 2 ). (such as Amberlite And its analogs are obtained in the form. In some other embodiments, the base can be provided in the form of an aqueous solution (aqueous base), such as a solution of about 2 N (eg, about 0.5 N solution, about 1 N solution, about 1.5 N solution, about 2.5 N solution, about 3 N to about 5). N solution, about 5 N to about 10 N solution). In some embodiments, the base can be an alkali metal hydroxide (eg, sodium hydroxide). In some embodiments, the base can be an aqueous 2 N NaOH solution. In some embodiments, the solvent can be methanol or tetrahydrofuran (THF). In some embodiments, the deprotection can be from about -10 ° C to about 60 ° C (eg, from about -10 ° C to about 0 ° C, from about 0 ° C to about 25 ° C, from about 25 ° C to about 45 ° C or from about 45 ° C to about It is carried out at a temperature of 60 ° C).

因此，本發明之另一態樣提供製備式F28化合物或其鹽之方法，其中R4 為F、Cl、Br或I；且n為1或2；該方法包括使式F29化合物或其鹽與磺醯胺及有機鹼反應以產生式F30化合物或其鹽，且使式F30化合物與鹼反應以產生式F28化合物。Accordingly, another aspect of the present invention to provide sample preparation method of the compound of Formula F28, or a salt thereof of, wherein R 4 is F, Cl, Br or I; and n is 1 or 2; which process comprises reacting a compound of Formula F29, or a salt thereof with The sulfonamide and the organic base are reacted to produce a compound of formula F30 or a salt thereof, and the compound of formula F30 is reacted with a base to yield a compound of formula F28.

在一些實施例中，R4 為Cl且n為1。In some embodiments, R 4 is Cl and n is 1.

在一些實施例中，R4 為Br且n為1。In some embodiments, R 4 is Br and n is 1.

在一些實施例中，式F29化合物之反應進一步包括將反應物加熱(諸如使用微波照射)。In some embodiments, the reaction of the compound of formula F29 further comprises heating the reactants (such as using microwave irradiation).

在另一態樣中，本發明提供藉由還原式F31化合物或其鹽來獲得式F29化合物之方法。在一些實施例中，可在碘化鈉、氯三甲基矽烷及甲醇之組合下進行還原。In another aspect, the invention provides a method of obtaining a compound of formula F29 by reducing a compound of formula F31 or a salt thereof. In some embodiments, the reduction can be carried out with a combination of sodium iodide, chlorotrimethylnonane, and methanol.

在本發明之另一態樣中，式F31化合物可如下獲得：用疊氮試劑處理式F32化合物或其鹽(其中L1 係選自烷基磺醯基、鹵烷基磺醯基及芳基磺醯基)以產生式F31化合物。In another aspect of the present invention, the compound of Formula F31 can be obtained as follows: with an azide reagent compound of Formula F32, or a salt thereof (wherein L 1 is selected from alkylsulfonyl group, a halo alkylsulfonyl group and an aryl group Sulfhydryl) to produce a compound of formula F31.

如本文所用，術語「烷基」當單獨使用或與其他部分術語一起使用時係指具有1至6個碳原子、1至4個碳原子或1至3個碳原子之直鏈或支鏈飽和烴基。實例烷基包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基及其類似基團。As used herein, the term "alkyl", when used alone or in conjunction with other parts of the term, refers to a straight or branched chain having from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, or from 1 to 3 carbon atoms. Hydrocarbyl group. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, and the like.

如本文所用之「烯基」係指具有一或多個碳碳雙鍵之烷基。實例烯基包括乙烯基、丙烯基及其類似基團。"Alkenyl" as used herein refers to an alkyl group having one or more carbon-carbon double bonds. Exemplary alkenyl groups include ethenyl, propenyl, and the like.

如本文所用，術語「芳基」係指可為具有6至14個碳原子之單環或多環的芳族烴基。實例芳基包括苯基、萘基、蒽基、菲基、茚滿基、茚基及其類似基團。As used herein, the term "aryl" refers to an aromatic hydrocarbon group which may be a monocyclic or polycyclic ring having 6 to 14 carbon atoms. Exemplary aryl groups include phenyl, naphthyl, anthracenyl, phenanthryl, indanyl, fluorenyl and the like.

如本文所用，術語「鹵烷基」當單獨使用或與其他部分一起使用時係指經一或多個獨立選自F、Cl、Br及I之鹵素原子取代之烷基。實例鹵烷基包括CF3 、CHF2 、CH2 CF3 、及其類似基團。As used herein, the term "haloalkyl" when used alone or in conjunction with other moieties, refers to an alkyl group substituted with one or more halogen atoms independently selected from the group consisting of F, Cl, Br, and I. Exemplary haloalkyl groups include CF 3 , CHF 2 , CH 2 CF 3 , and the like.

如本文所用，術語「烷氧基」係指-O-烷基。實例烷氧基包括甲氧基、乙氧基、丙氧基(例如正丙氧基及異丙氧基)、第三丁氧基及其類似基團。As used herein, the term "alkoxy" refers to -O-alkyl. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), tert-butoxy, and the like.

如本文所用，「烷基胺」係指經烷基取代之胺基(NH2 )。實例烷基胺基包括甲胺基、己胺基及其類似基團。As used herein, the substituent "alkylamine" means an alkyl group (NH 2). Exemplary alkylamino groups include methylamino, hexylamino and the like.

如本文所用，「三烷基胺」係指經三個烷基取代之氮原子。實例三烷基胺基包括三甲基胺基、三乙基胺基及其類似基團。As used herein, "trialkylamine" refers to a nitrogen atom substituted with three alkyl groups. Examples Trialkylamino groups include trimethylamino, triethylamine and the like.

如本文所用，術語「烷氧羰基」係指經烷氧基取代之CO：-C(O)-O-烷基。實例烷氧羰基包括乙氧羰基、第三丁氧羰基(Boc)、苯甲氧羰基(Cbz)、9-茀基甲氧羰基(Fmoc)及其類似基團。As used herein, the term "alkoxycarbonyl" refers to a C:-C(O)-O-alkyl group substituted with an alkoxy group. Exemplary alkoxycarbonyl groups include ethoxycarbonyl, third butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc) and the like.

如本文所用，術語「烷基磺醯基」係指經烷基取代之磺醯基：烷基S(O)2 -。實例烷基磺醯基包括甲烷磺醯基、乙烷磺醯基及其類似基團。As used herein, the term "alkylsulfonyl" refers to an alkyl substituted sulfonyl group: alkyl S(O) 2- . Examples Alkylsulfonyl includes methanesulfonyl, ethanesulfonyl and the like.

如本文所用，術語「鹵烷基磺醯基」係指經鹵烷基取代之磺醯基。實例鹵烷基磺醯基包括三氟甲烷磺醯基、1,1,1-三氟乙烷磺醯基及其類似基團。As used herein, the term "haloalkylsulfonyl" refers to a sulfonyl group substituted with a haloalkyl group. Examples Haloalkylsulfonyl includes trifluoromethanesulfonyl, 1,1,1-trifluoroethanesulfonyl and the like.

如本文所用，術語「芳基磺醯基」係指經芳基或經取代芳基取代之磺醯基，其中芳基上之取代基係選自鹵基、硝基、C1-4 烷基及C1-4 鹵烷基。As used herein, the term "arylsulfonyl" refers to a sulfonyl group substituted with an aryl or substituted aryl group, wherein the substituent on the aryl group is selected from halo, nitro, C 1-4 alkyl. And C 1-4 haloalkyl.

如本文所用，術語「雜環鹼」係指視情況經取代之4至14員雜環，其中至少一個成環成員為氮原子。雜環鹼可為芳族或非芳族。實例雜環鹼包括吡啶、吡咯啶、哌啶、嗎啉等鹼。雜環上之實例取代基包括F、Cl、Br、C1-4 烷基及C1-4 鹵烷基。As used herein, the term "heterocyclic base" refers to a 4- to 14-membered heterocyclic ring which is optionally substituted, wherein at least one of the ring-forming members is a nitrogen atom. The heterocyclic base can be aromatic or non-aromatic. Examples of heterocyclic bases include bases such as pyridine, pyrrolidine, piperidine, morpholine and the like. Exemplary substituents on the heterocyclic ring include F, Cl, Br, C 1-4 alkyl and C 1-4 haloalkyl.

使用方法Instructions

本發明化合物可抑制酶吲哚胺-2,3-雙加氧酶(IDO)之活性。舉例而言，藉由投與抑制量之本發明化合物，本發明化合物可用於抑制細胞中或需要調節酶之個體中的IDO活性。The compounds of the invention inhibit the activity of the enzyme indoleamine-2,3-dioxygenase (IDO). For example, a compound of the invention can be used to inhibit IDO activity in a cell or in an individual in need of modulation of the enzyme by administering an inhibitory amount of a compound of the invention.

本發明進一步提供在含有表現IDO之細胞的系統(諸如組織、活器官或細胞培養物)中抑制色胺酸降解之方法。在一些實施例中，本發明提供藉由投與有效量之本文中所提供之化合物或組合物來改變(例如增加)胞外色胺酸含量之方法。量測色胺酸含量及色胺酸降解之方法為此項技術中之常規方法。The invention further provides methods of inhibiting degradation of tryptophan in a system comprising cells expressing IDO, such as tissues, living organs or cell cultures. In some embodiments, the invention provides methods of altering (eg, increasing) extracellular tryptophan acid content by administering an effective amount of a compound or composition provided herein. Methods for measuring tryptophan acid content and tryptophan degradation are conventional methods in the art.

本發明進一步提供藉由向患者投與有效量之本文中所述之化合物或組合物來抑制患者之免疫抑制(諸如IDO介導之免疫抑制)之方法。IDO介導之免疫抑制與例如癌症、腫瘤生長、癌轉移、病毒感染、病毒複製等疾病有關。The invention further provides methods of inhibiting immunosuppression (such as IDO-mediated immunosuppression) in a patient by administering to the patient an effective amount of a compound or composition described herein. IDO-mediated immunosuppression is associated with diseases such as cancer, tumor growth, cancer metastasis, viral infection, viral replication, and the like.

本發明進一步提供藉由向需要該治療之個體投與治療有效量或治療有效劑量之本發明化合物或其醫藥組合物來治療個體(例如患者)中與IDO活性或表現(包括異常活性及/或過度表現)相關之疾病的方法。實例疾病可包括與IDO酶之表現或活性(諸如過度表現或異常活性)直接或間接關聯之任何疾病、病症或病狀。IDO相關疾病亦可包括藉由調節酶活性可加以預防、改善或治癒之任何疾病、病症或病況。IDO相關疾病的實例包括癌症、病毒感染(諸如HIV感染、HCV感染)、抑鬱症、神經退化性病症(諸如阿茲海默氏病(Alzheimer's disease)及亨廷頓氏病(Huntington's disease))、創傷、年齡相關性白內障、器官移植(例如器官移植排斥反應)及自體免疫疾病(包括哮喘、類風濕性關節炎、多發性硬化症、過敏性炎症、發炎性腸病、牛皮癬及全身性紅斑狼瘡)。可由本文方法治療之實例癌症包括結腸癌、胰腺癌、乳癌、***癌、肺癌、腦癌、卵巢癌、子宮頸癌、睪丸癌、腎癌、頭頸癌、淋巴瘤、白血病、黑素瘤及其類似癌症。本發明化合物亦可適用於治療肥胖症及局部缺血。The invention further provides for treating a subject (eg, a patient) with IDO activity or performance (including abnormal activity and/or by administering a therapeutically effective amount or a therapeutically effective amount of a compound of the invention or a pharmaceutical composition thereof to an individual in need of such treatment. Over-expression) methods associated with the disease. An example disease can include any disease, disorder, or condition that is directly or indirectly associated with the performance or activity of an IDO enzyme, such as overexpression or abnormal activity. IDO-related diseases can also include any disease, disorder, or condition that can be prevented, ameliorated, or cured by modulating enzyme activity. Examples of IDO-related diseases include cancer, viral infections (such as HIV infection, HCV infection), depression, neurodegenerative disorders (such as Alzheimer's disease and Huntington's disease), trauma, Age-related cataracts, organ transplants (eg, organ transplant rejection), and autoimmune diseases (including asthma, rheumatoid arthritis, multiple sclerosis, allergic inflammation, inflammatory bowel disease, psoriasis, and systemic lupus erythematosus) . Examples of cancers that can be treated by the methods herein include colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, renal cancer, head and neck cancer, lymphoma, leukemia, melanoma and Similar to cancer. The compounds of the invention may also be useful in the treatment of obesity and ischemia.

如本文所用，術語「細胞」欲指活體外、離體或活體內之細胞。在一些實施例中，離體細胞可為自諸如哺乳動物之生物體所切除之組織樣本的一部分。在一些實施例中，活體外細胞可為細胞培養物中之細胞。在一些實施例中，活體內細胞為在諸如哺乳動物之生物體中生存之細胞。As used herein, the term "cell" is intended to mean a cell that is in vitro, ex vivo or in vivo. In some embodiments, the ex vivo cells can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, the ex vivo cells can be cells in cell culture. In some embodiments, the cells in vivo are cells that survive in an organism such as a mammal.

如本文所用，術語「接觸」係指使指定部分在活體外系統或活體內系統中集合在一起。舉例而言，使IDO酶與本發明化合物「接觸」包括向具有IDO之個體或患者(諸如人類)投與本發明化合物以及(例如)將本發明化合物引入含有細胞製劑或經純化製劑的樣本中，該製劑含有IDO酶。As used herein, the term "contacting" means bringing a specified portion together in an in vitro or in vivo system. For example, "contacting" an IDO enzyme with a compound of the invention includes administering a compound of the invention to an individual or patient having an IDO, such as a human, and, for example, introducing a compound of the invention into a sample comprising a cell preparation or a purified preparation. The formulation contains an IDO enzyme.

如本文所用，可互換使用之術語「個體」或「患者」係指任何動物，包括哺乳動物，較佳為小鼠、大鼠、其他齧齒動物、兔、犬、貓、豬、牛、綿羊、馬或靈長類動物，且最佳為人類。As used herein, the terms "individual" or "patient" are used interchangeably to refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, Horse or primate, and the best is human.

如本文中所用，「治療有效量」一詞係指在組織、系統、動物、個體或人體中誘發生物學或醫學反應之活性化合物或藥劑的量，該反應正為研究者、獸醫、醫生或其他臨床醫師所尋求。As used herein, the term "therapeutically effective amount" refers to an amount of an active compound or agent that elicits a biological or medical response in a tissue, system, animal, individual or human, which is being investigated by a researcher, veterinarian, doctor or Seek by other clinicians.

如本文所用，術語「治療」係指1)預防疾病，例如預防可易患疾病、病狀或病症但尚未經歷或顯示疾病之病理或症狀之個體的疾病、病狀或病症；2)抑制疾病，例如抑制正經歷或顯示疾病、病狀或病症之病理或症狀之個體之疾病、病狀或病症(亦即阻止病理及/或征狀進一步發展)；或3)改善疾病，例如改善正經歷或顯示疾病、病狀或病症之病理或症狀之個體的疾病、病狀或病症(亦即使病理及/或症狀好轉)。As used herein, the term "treating" refers to 1) preventing a disease, for example, preventing a disease, condition or disorder in an individual susceptible to a disease, condition or condition but having not experienced or manifested the path or symptom of the disease; 2) inhibiting the disease For example, inhibiting a disease, condition or disorder of an individual who is experiencing or exhibiting a pathology or symptom of a disease, condition or disorder (ie, preventing further progression of the pathology and/or symptoms); or 3) improving the disease, such as improving the positive experience. Or a disease, condition or disorder (even if the pathology and/or symptoms are ameliorated) of the individual showing the pathology or symptoms of the disease, condition or condition.

組合療法Combination therapy

一或多種其他藥劑或治療方法(諸如抗病毒劑、化學治療劑或其他抗癌劑、免疫增強劑、免疫抑制劑、輻射、抗腫瘤及抗病毒疫苗、細胞因子療法(例如IL2、GM-CSF等)及/或酪胺酸激酶抑制劑)可與本發明化合物組合用於治療IDO相關性疾病、病症或病狀。該等藥劑可與本發明化合物組合為單一劑型，或該等藥劑可以獨立劑型同時或依序投與。One or more other agents or treatments (such as antiviral agents, chemotherapeutic or other anticancer agents, immunopotentiators, immunosuppressants, radiation, anti-tumor and anti-viral vaccines, cytokine therapies (eg IL2, GM-CSF) And/or a tyrosine kinase inhibitor) can be used in combination with a compound of the invention for the treatment of an IDO related disease, disorder or condition. The agents may be combined with the compounds of the invention in a single dosage form, or such agents may be administered simultaneously or sequentially in separate dosage forms.

預期可與本發明化合物組合使用之合適抗病毒劑可包含核苷及核苷酸逆轉錄酶抑制劑(NRTI)、非核苷逆轉錄酶抑制劑(NNRTI)、蛋白酶抑制劑及其他抗病毒藥物。Suitable antiviral agents contemplated for use in combination with the compounds of the invention may include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and other antiviral drugs.

合適NRTI之實例包括齊多夫定(zidovudine)(AZT)；去羥肌苷(didanosine)(ddl)；紮西他濱(zalcitabine)(ddC)；司他夫定(stavudine)(d4T)；拉米夫定(lamivudine)(3TC)；阿巴卡韋(abacavir)(1592U89)；阿德福韋酯(adefovir dipivoxil)[雙(POM)-PMEA]；洛布卡韋(lobucavir)(BMS-180194)；BCH-10652；艾米特賓(emitricitabine)[(-)-FTC]；β-L-FD4(亦稱作β-L-D4C且命名為β-L-2',3'-二脫氧-5-氟-胞啶)；DAPD((-)-β-D-2,6-二胺基-嘌呤二氧戊環)；及洛德腺苷(lodenosine)(FddA)。典型的合適NNRTI包括奈偉拉平(nevirapine)(BI-RG-587)；地拉韋啶(delaviradine)(BHAP，U-90152)；依法韋侖(efavirenz)(DMP-266)；PNU-142721；AG-1549；MKC-442(1-(乙氧基-甲基)-5-(1-甲基乙基)-6-(苯基甲基)-(2,4(1H,3H)-嘧啶二酮)；及(+)-胡桐素A((+)-calanolide A)(NSC-675451)及(+)-胡桐素B。典型的合適蛋白酶抑制劑包括沙喹那韋(saquinavir)(Ro 31-8959)；利托那韋(ritonavir)(ABT-538)；茚地那韋(indinavir)(MK-639)；奈非那韋(nelfnavir)(AG-1343)；安普那韋(amprenavir)(141W94)；拉西那韋(lasinavir)(BMS-234475)；DMP-450；BMS-2322623；ABT-378；及AG-1549。其他抗病毒劑包括羥基脲、利巴韋林(ribavirin)、IL-2、IL-12、五氟苷(pentafuside)及Yissum Project第11607號。Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); Lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [double (POM)-PMEA]; lobucavir (BMS-180194) BCH-10652; emitricitabine [(-)-FTC]; β-L-FD4 (also known as β-L-D4C and named β-L-2', 3'-dideoxy -5-fluoro-cytidine; DAPD ((-)-β-D-2,6-diamino-fluorenyldioxolane); and lodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidine Diketone); and (+)-Huotin A ((+)-calanolide A) (NSC-675451) and (+)-Hutongsu B. Typical suitable protease inhibitors include saquinavir (Ro 31-) 8959); ritonavir (ABT-538); indinavir (MK-639); nelfnavir (AG-1343); amprenavir (amprenavir) 141W94); lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549. Other antiviral agents include hydroxyurea, ribavirin, IL -2, IL-12, pentafuside and Yissum Project No. 11607.

適合化學治療劑或其他抗癌劑包括例如烷基化劑(包括(但不限於)氮芥、伸乙亞胺衍生物、烷基磺酸鹽、亞硝基脲及三氮烯)，諸如尿嘧啶芥(uracil mustard)、氮芥(chlormethine)、環磷醯胺(CytoxanTM )、異環磷醯胺、美法侖(melphalan)、苯丁酸氮芥(chlorambucil)、哌泊溴烷(pipobroman)、三伸乙蜜胺(triethylene-melamine)、三伸乙基硫代磷胺、白消安(busulfan)、卡莫司汀(carmustine)、洛莫司汀(lomustine)、鏈佐星(streptozocin)、達卡巴嗪(dacarbazine)及替莫唑胺(temozolomide)。Suitable chemotherapeutic agents or other anticancer agents include, for example, alkylating agents including, but not limited to, nitrogen mustard, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes, such as urine. mustard pyrimidine (uracil mustard), nitrogen mustards (chlormethine), cyclophosphamide (Cytoxan TM), iso cyclophosphamide, melphalan (melphalan), chlorambucil (chlorambucil), pipobroman (pipobroman ), triethylene-melamine, tri-ethyl thiophosphoramide, busulfan, carmustine, lomustine, streptozocin ), dacarbazine and temozolomide.

在黑素瘤治療中，適合與本發明化合物組合使用之藥劑包括：達卡巴嗪(DTIC)，視情況與其他化學治療藥物(諸如卡莫司汀(BCNU)及順鉑)一起；由DTIC、BCNU、順鉑及他莫昔芬(tamoxifen)組成之「Dartmouth療法」；順鉑、長春鹼(vinblastine)及DTIC之組合；或替莫唑胺(temozolomide)。本發明化合物亦可與免疫治療藥物(包括細胞因子，諸如干擾素α、介白素2及腫瘤壞死因子(TNF))組合用於治療黑素瘤。In the treatment of melanoma, agents suitable for use in combination with the compounds of the invention include: dacarbazine (DTIC), optionally with other chemotherapeutic drugs (such as carmustine (BCNU) and cisplatin); by DTIC, "Dartmouth therapy" consisting of BCNU, cisplatin and tamoxifen; a combination of cisplatin, vinblastine and DTIC; or temozolomide. The compounds of the invention may also be used in combination with immunotherapeutic drugs, including cytokines such as interferon alpha, interleukin 2 and tumor necrosis factor (TNF), for the treatment of melanoma.

本發明化合物亦可與疫苗療法組合用於治療黑素瘤。在某些方面，抗黑素瘤疫苗類似於用於預防病毒引起之疾病(諸如小兒麻痺症、麻疹及流行性腮腺炎)的抗病毒疫苗。稱為抗原之弱化黑素瘤細胞或黑素瘤細胞之部分可注射於患者以刺激身體免疫系統破壞黑素瘤細胞。The compounds of the invention may also be used in combination with vaccine therapy for the treatment of melanoma. In certain aspects, the anti-melanoma vaccine is similar to an antiviral vaccine for preventing diseases caused by the virus, such as polio, measles and mumps. A portion of the attenuated melanoma cells or melanoma cells, called antigens, can be injected into the patient to stimulate the body's immune system to destroy melanoma cells.

侷限於手臂或腿之黑素瘤亦可使用高溫隔離肢體灌注技術以包括一或多種本發明化合物之藥劑組合治療。此治療方案係使所涉及肢體之循環暫時與身體其餘部分隔開且將高劑量化學治療劑注入輸往該肢體之動脈內，從而向腫瘤區域提供高劑量化學治療劑而不使內部器官暴露於此等劑量，否則可能引起嚴重副作用。一般將流體溫至102℉至104℉。美法侖為此化學治療程序中最常用之藥物。此藥可與另一種稱為腫瘤壞死因子(TNF)(參看有關細胞因子的部分)之藥劑一起給予。Melanoma confined to the arm or leg can also be treated with a combination of agents comprising one or more compounds of the invention using a high temperature isolated limb perfusion technique. This treatment regimen temporarily separates the circulation of the limb involved from the rest of the body and injects a high dose of chemotherapeutic agent into the artery that is delivered to the limb, thereby providing a high dose of chemotherapeutic agent to the tumor area without exposing the internal organs to These doses may otherwise cause serious side effects. The fluid is typically warmed to between 102 °F and 104 °F. Melphalan is the most commonly used drug in this chemotherapy program. This drug can be administered with another agent called tumor necrosis factor (TNF) (see section on cytokines).

適合化學治療劑或其他抗癌劑包括例如抗代謝物(包括(但不限於)葉酸拮抗劑、嘧啶類似物、嘌呤類似物及腺苷去胺酶抑制劑)，諸如甲胺喋呤(methotrexate)、5-氟尿嘧啶、氟尿苷(floxuridine)、阿糖胞苷(cytarabine)、6-巰基嘌呤、6-硫鳥嘌呤、磷酸氟達拉濱(fludarabine phos-phate)、噴司他丁(pentostatine)及吉西他濱(gemcita-bine)。Suitable chemotherapeutic agents or other anticancer agents include, for example, antimetabolites (including but not limited to folic acid antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors), such as methotrexate. , 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phos-phate, pentostatine And gemcitabine (gemcita-bine).

合適化學治療劑或其他抗癌劑另外包括(例如)某些天然產物及其衍生物(例如長春花屬生物鹼、抗腫瘤抗生素、酶、淋巴因子(lymphokine)及表鬼臼毒素(epipodophyllotoxin))，諸如長春鹼(vinblastine)、長春新鹼(vincristine)、長春地辛(vindesine)、博來黴素(bleomycin)、放線菌素D(dactinomycin)、道諾黴素(daunorubicin)、多柔比星(doxorubicin)、表柔比星(epirubicin)、伊達比星(idarubicin)、阿糖胞苷、紫杉醇(TAXOLTM )、光神黴素(mithramycin)、脫氧考福黴素(deoxycoformycin)、絲裂黴素-C(mitomycin-C)、L-天冬醯胺酶、干擾素(尤其IFN-a)、依託泊苷(etoposide)及替尼泊苷(teniposide)。Suitable chemotherapeutic agents or other anticancer agents additionally include, for example, certain natural products and derivatives thereof (eg, vinca alkaloids, antitumor antibiotics, enzymes, lymphokine, and epipodophyllotoxin) Such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin (doxorubicin), epirubicin (epirubicin), idarubicin (idarubicin), cytarabine, paclitaxel (tAXOL TM), mithramycin (mithramycin), Cobh deoxy doxorubicin (deoxycoformycin), mitomycin M-C (mitomycin-C), L-aspartate, interferon (especially IFN-a), etoposide and teniposide.

其他細胞毒性劑包括那韋比尼(navelbene)、CPT-11、阿那曲唑(anastrazole)、來曲唑(letrazole)、卡培他濱(capecitabine)、瑞洛昔芬(reloxafine)、環磷醯胺、異環磷醯胺及屈洛昔芬(droloxafine)。Other cytotoxic agents include navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, cyclophosphazene Amine, ifosfamide and droloxenefine.

亦合適之細胞毒性劑為(諸如)表鬼臼毒素；抗贅生性酶；拓撲異構酶抑制劑；丙卡巴肼(procarbazine)；米托蒽醌(mitoxantrone)；鉑配位錯合物，諸如順鉑及卡鉑(carboplatin)；生物反應調節劑；生長抑制劑；抗激素治療劑；甲醯四氫葉酸(leucovorin)；替加氟(tegafur)；及造血生長因子。Also suitable cytotoxic agents are, for example, epipodophyllotoxin; anti-neoplastic enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum coordination complexes, such as Cisplatin and carboplatin; biological response modifiers; growth inhibitors; antihormonal therapeutics; leucovorin; tegafur; and hematopoietic growth factors.

其他抗癌劑包括抗體治療劑，諸如曲妥珠單抗(trastuzumab)(Herceptin)、抗協同刺激分子(諸如CTLA-4、4-1BB及PD-1)之抗體，或抗細胞因子(IL-10、TGF-β等細胞因子)之抗體。Other anticancer agents include antibody therapeutics, such as trastuzumab (Herceptin), antibodies against costimulatory molecules (such as CTLA-4, 4-1BB, and PD-1), or anti-cytokines (IL- 10. Antibodies against cytokines such as TGF-β.

其他抗癌劑亦包括阻斷免疫細胞遷移之彼等藥劑，諸如趨化因子受體(包括CCR2及CCR4)之拮抗劑。Other anticancer agents also include agents that block the migration of immune cells, such as antagonists of chemokine receptors, including CCR2 and CCR4.

其他抗癌劑亦包括強化免疫系統之彼等抗癌劑(諸如佐劑或授受性T細胞轉移劑)。Other anticancer agents also include anti-cancer agents (such as adjuvants or conferring T cell transfer agents) that potentiate the immune system.

抗癌疫苗包括樹突狀細胞、合成肽、DNA疫苗及重組病毒。Anticancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses.

熟習此項技術者已知多數此等化學治療劑之安全且有效投與方法。此外，其投與描述於標準文獻中。舉例而言，多種化學治療劑之投與描述於「Physicians' Desk Reference」(PDR，例如，1996版，Medical Economics Company,Montvale,NJ)中，其揭示內容以引用的方式併入本文中，如同闡述其全文一樣。A safe and effective method of administration of most of these chemotherapeutic agents is known to those skilled in the art. In addition, its contribution is described in the standard literature. For example, the administration of various chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, eg, 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference. Explain the same as the full text.

醫藥調配物及劑型Pharmaceutical formulations and dosage forms

當用作藥物時，本發明化合物可以醫藥組合物形式投與，該形式為本發明化合物與醫藥學上可接受之載劑的組合。此等組合物可以醫藥技術中熟知之方式製備，且視需要局部或全身治療及待治療之區域而定可藉由多種途徑投與。投藥可為局部(包括眼及黏膜(包括鼻內、***及直腸傳遞))、肺部(例如包括藉由噴霧器將散劑或霧劑吸入或吹入；氣管內、鼻內、表皮及經皮)、經眼、經口或非經腸方式。經眼傳遞之方法可包括局部投與(滴眼劑)、結膜下、眼周或玻璃體內注射或藉由手術置於結膜囊中之氣囊導管或眼內***物引入。非經腸投與包括靜脈內、動脈內、皮下、腹膜內或肌肉內注射或輸注；或顱內(例如鞘內腔或心室內)投與。非經腸投與可為單次劑量之形式，或可(例如)藉由連續灌注泵進行。用於局部投與之醫藥組合物及調配物可包括經皮貼片、軟膏、洗劑、乳膏、凝膠、滴劑、栓劑、噴霧劑、液體及散劑。習知醫藥載劑、水性、粉末或油性基質、增稠劑及其類似物可為必需的或所需的。When used as a medicament, the compounds of the invention may be administered in the form of a pharmaceutical composition which is a combination of a compound of the invention and a pharmaceutically acceptable carrier. Such compositions may be prepared in a manner well known in the art of pharmacy and may be administered by a variety of routes depending on the local or systemic treatment and the area to be treated. Administration may be local (including eye and mucous membranes (including intranasal, vaginal and rectal)), lungs (for example including inhalation or insufflation of powder or aerosol by nebulizer; intratracheal, intranasal, epidermal and transdermal) , by eye, oral or parenteral. Methods of transocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injections or introduction of balloon catheters or intraocular inserts placed surgically in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial (eg, intrathecal or intraventricular) administration. Parenteral administration can be in the form of a single dose or can be carried out, for example, by a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desired.

本發明亦包括醫藥組合物，其含有作為活性成份之以上一或多種本發明化合物與一或多種醫藥學上可接受之載劑之組合。製備本發明組合物時，通常將活性成份與賦形劑混合、藉由賦形劑稀釋或封閉於呈(例如)膠囊、藥囊、紙或其他容器之形式的該載體中。當賦形劑用作稀釋劑時，其可為固體、半固體或液體材料，其充當活性成份之媒劑、載劑或介質。因此，組合物可呈以下形式：錠劑、丸劑、散劑、***劑、藥囊、扁膠劑、酏劑、懸浮液、乳液、溶液、糖漿、霧劑(呈固體形式或於液體介質中)、含有(例如)高達10重量%之活性化合物之軟膏、軟質及硬質明膠膠囊、栓劑、無菌可注射溶液及無菌封裝散劑。The invention also includes pharmaceutical compositions comprising as an active ingredient a combination of one or more of the compounds of the invention together with one or more pharmaceutically acceptable carriers. In preparing the compositions of the present invention, the active ingredient is usually mixed with excipients, diluted by excipients or enclosed in such carriers in the form of, for example, capsules, sachets, paper or other containers. When the excipient serves as a diluent, it can be a solid, semi-solid or liquid material which acts as a vehicle, carrier or medium for the active ingredient. Thus, the composition may be in the form of a tablet, a pill, a powder, a buccal, a sachet, a blister, an elixir, a suspension, an emulsion, a solution, a syrup, an aerosol (in solid form or in a liquid medium). An ointment containing, for example, up to 10% by weight of active compound, a soft and hard gelatin capsule, a suppository, a sterile injectable solution, and a sterile encapsulated powder.

製備調配物時，在與其他成份合併之前，可將活性化合物研磨以提供適當粒徑。若活性化合物實質上不溶，則可將其研磨至小於200目之粒徑。若活性化合物實質上為水溶性的，則可藉由研磨調節粒徑以提供在調配物中之實質均一分布，例如約40目。When preparing the formulation, the active compound can be ground to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be ground to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantial uniform distribution in the formulation, for example about 40 mesh.

合適賦形劑之一些實例包括乳糖、右旋糖、蔗糖、山梨糖醇、甘露糖醇、澱粉、***膠、磷酸鈣、海藻酸鹽、黃蓍膠、明膠、矽酸鈣、微晶纖維素、聚乙烯吡咯啶酮、纖維素、水、糖漿及甲基纖維素。調配物可另外包括：潤滑劑，諸如滑石、硬脂酸鎂及礦物油；濕潤劑；乳化劑及懸浮劑；防腐劑，諸如苯甲酸甲酯及苯甲酸丙基羥基酯；甜味劑；及調味劑。本發明之組合物可經調配以便在藉由使用此項技術中已知之程序投與患者後提供活性成份之快速、持續或延遲釋放。Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium citrate, microcrystalline cellulose. , polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. Formulations may additionally include: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl benzoate and propyl hydroxy benzoate; sweeteners; Flavoring agent. The compositions of the present invention can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a patient by procedures known in the art.

組合物可調配為單位劑型，各劑量含有約5 mg至約100 mg、更一般約10 mg至約30 mg之活性成份。術語「單位劑型」係指適用於人類個體及其他哺乳動物、呈單位劑量形式的物理離散單元，各單元含有經計算可產生所要治療作用之預定量之活性物質以及合適醫藥賦形劑。The compositions may be formulated in unit dosage form, each containing from about 5 mg to about 100 mg, more typically from about 10 mg to about 30 mg of the active ingredient. The term "unit dosage form" refers to physically discrete units in unit dosage form suitable for use in human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, and a suitable pharmaceutical excipient.

活性化合物可在廣泛劑量範圍內有效且一般係以醫藥學上有效之量投與。然而，應理解實際投與之化合物之量一般將由醫師根據相關情形判定，該等情形包括待治療之病狀、所選投與途徑、所投與之實際化合物、個別患者之年齡、體重及反應、患者症狀之嚴重程度及其類似情形。The active compounds are effective over a wide range of dosages and are generally administered in a pharmaceutically effective amount. However, it is to be understood that the amount of the compound actually administered will generally be determined by the physician in light of the circumstances, including the condition to be treated, the route of administration chosen, the actual compound administered, the age, weight and response of the individual patient. The severity of the patient's symptoms and the like.

製備固體組合物(諸如錠劑)時，將主要活性成份與醫藥賦形劑混合以形成含有本發明化合物之均質混合物的固體預調配組合物。當稱此等預調配組合物為均質時，活性成份通常均勻分散於整個組合物中以使得該組合物可容易地再分為諸如錠劑、丸劑及膠囊之等效單位劑型。隨後將此固體預調配物再分為含有(例如)0.1 mg至約500 mg本發明之活性成份的上述類型之單位劑型。In preparing a solid composition, such as a troche, the active ingredient is mixed with a pharmaceutical excipient to form a solid pre-formulation composition containing a homogeneous mixture of the compound of the invention. When such pre-formulation compositions are said to be homogeneous, the active ingredient will usually be uniformly dispersed throughout the composition so that the composition can be readily subdivided into equivalent unit dosage forms such as lozenges, pills, and capsules. This solid pre-formulation is then subdivided into unit dosage forms of the type described above containing, for example, from 0.1 mg to about 500 mg of the active ingredient of the present invention.

本發明之錠劑或丸劑可經包衣或另外混配以提供具有長效優點之劑型。舉例而言，錠劑或丸劑可包含內部劑量組份及外部劑量組份，後者以包膜形式覆蓋於前者上。兩種組份可由腸衣層隔開，腸衣層用於阻止在胃中崩解且允許內部組份完整進入十二指腸中或延遲釋放。該等腸衣層或包衣可使用多種材料，該等材料包括多種聚合物酸及聚合物酸與諸如蟲膠、十六烷醇及醋酸纖維素之材料的混合物。The lozenges or pills of the present invention may be coated or otherwise compounded to provide a dosage form having long-lasting advantages. For example, a lozenge or pill can comprise an inner dosage component and an outer dosage component, the latter covering the former in the form of a coating. The two components can be separated by an enteric layer which serves to prevent disintegration in the stomach and allows the internal component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for the casing layers or coatings, including a plurality of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

本發明化合物及組合物可併入其中以經口或藉由注射投與之液體形式包括水溶液、適當調味之糖漿、水性或油性懸浮液，及具有食用油(諸如棉籽油、芝麻油、椰子油或花生油)之調味乳液，以及酏劑及類似醫藥媒劑。The compounds and compositions of the present invention may be incorporated into liquid forms for oral or by injection, including aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and with edible oils such as cottonseed oil, sesame oil, coconut oil or Flavored lotion of peanut oil), as well as tinctures and similar medical agents.

用於吸入或吹入之組合物包括存於醫藥學上可接受之水性或有機溶劑或其混合物中之溶液及懸浮液，及散劑。液體或固體組合物可含有如上文所述之合適醫藥學上可接受之賦形劑。在一些實施例中，組合物係藉由經口或經鼻呼吸途徑投與以達成局部或全身性作用。可使用惰性氣體使組合物霧化。霧化溶液可直接自噴霧裝置吸取或該噴霧裝置可附接至面罩幕或間歇正壓力呼吸機上。溶液、懸浮液或粉末組合物可自以適當方式傳遞調配物之裝置經口或經鼻投與。Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered by oral or nasal respiratory route to achieve a local or systemic effect. The composition can be atomized using an inert gas. The atomized solution can be drawn directly from the spray device or the spray device can be attached to a mask or intermittent positive pressure ventilator. The solution, suspension or powder composition can be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

投與患者之化合物或組合物之量將視以下因素而變：投與何物、投與目的(諸如預防或治療)、患者狀態、投與方式及其類似因素。在治療性應用中，組合物可以足以治癒或至少部分抑制疾病及其併發症之症狀之量投與已罹患疾病之患者。有效劑量將視所治療之疾病狀況以及主治臨床醫師之判斷而定，視諸如疾病嚴重程度、患者之年齡、體重及一般狀況及其類似因素而定。The amount of a compound or composition administered to a patient will vary depending on factors such as what is administered, the purpose of the administration (such as prevention or treatment), the state of the patient, the mode of administration, and the like. In therapeutic applications, the composition can be administered to a patient already suffering from the disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dosage will depend on the condition being treated and the judgment of the attending clinician, depending on the severity of the disease, the age, weight and general condition of the patient and the like.

投與患者之組合物可呈上述醫藥組合物之形式。此等組合物可藉由習知滅菌技術來滅菌，或可經無菌過濾。水溶液可經封裝以原樣使用或經凍乾，凍乾製劑係在投與之前與無菌水性載劑組合。化合物製劑之pH值通常介於3與11之間，更佳為5至9且最佳為7至8。應理解使用某些前述賦形劑、載劑或穩定劑將引起醫藥鹽之形成。The composition for administration to a patient can be in the form of a pharmaceutical composition as described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. The aqueous solution can be packaged for use as is or lyophilized, and the lyophilized formulation is combined with a sterile aqueous carrier prior to administration. The pH of the compound preparation is usually between 3 and 11, more preferably 5 to 9, and most preferably 7 to 8. It will be appreciated that the use of certain of the foregoing excipients, carriers or stabilizers will result in the formation of a pharmaceutical salt.

本發明化合物的治療劑量可根據(例如)治療所針對之特定用途、化合物之投與方式、患者之健康及狀況及處方醫師之判斷而改變。本發明化合物在醫藥組合物中之比例或濃度可視多種因素而改變，該等因素包括劑量、化學特性(例如疏水性)及投與途徑。舉例而言，本發明化合物可提供於含有約0.1至約10% w/v化合物之水性生理緩衝溶液中以便非經腸投與。一些典型劑量範圍為每日每公斤體重約1 μg至約1 g。在一些實施例中，劑量範圍為每日每公斤體重約0.01 mg至約100 mg。劑量可視諸如以下變數而定：疾病或病症之類型及進展程度、特定患者之整體健康狀況、所選化合物之相對生物功效、賦形劑之調配及其投與途徑。可經由來源於活體外或動物模型測試系統之劑量-反應曲線來推斷有效劑量。The therapeutic dose of a compound of the invention may vary depending, for example, on the particular use for which the treatment is to be administered, the manner in which the compound is administered, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of a compound of the invention in a pharmaceutical composition can vary depending on a number of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, a compound of the invention can be provided in an aqueous physiological buffer solution containing from about 0.1 to about 10% w/v of a compound for parenteral administration. Some typical dosage ranges range from about 1 μg to about 1 g per kilogram of body weight per day. In some embodiments, the dosage range is from about 0.01 mg to about 100 mg per kilogram of body weight per day. The dosage may depend on such variables as the type and progression of the disease or condition, the overall health of the particular patient, the relative biological efficacy of the selected compound, the formulation of the excipient, and the route of administration thereof. The effective dose can be inferred via a dose-response curve derived from an in vitro or animal model test system.

本發明化合物亦可與一或多種其他活性成份組合調配，該等活性成份可包括任何藥劑，諸如抗病毒劑、疫苗、抗體、免疫增強劑、免疫抑制劑、消炎劑及其類似物。The compounds of the invention may also be formulated in combination with one or more other active ingredients, which may include any agents such as antiviral agents, vaccines, antibodies, immunopotentiators, immunosuppressants, anti-inflammatory agents, and the like.

標記化合物及檢定方法Labeling compound and assay method

本發明之另一態樣係關於經螢光染料、自旋標記、重金屬或放射性標記之本發明化合物，其不僅適用於成像，且亦適用於活體外與活體內檢定中以定位及定量組織樣本(包括人類)中之IDO酶，且藉由經標記化合物之抑制結合用於鑑別IDO酶配體。因此，本發明包括含有該等經標記化合物之IDO酶檢定。Another aspect of the invention pertains to fluorescent dyes, spin labels, heavy metals or radioactively labeled compounds of the invention which are not only suitable for imaging, but are also suitable for use in in vitro and in vivo assays for localization and quantification of tissue samples. The IDO enzyme in (including humans) is used to identify IDO enzyme ligands by inhibition of the labeled compound. Accordingly, the invention includes IDO enzyme assays containing such labeled compounds.

本發明進一步包括經同位素標記之式I化合物。「同位素」或「放射性標記」化合物為其中一或多個原子經具有不同於自然界中通常存在(亦即天然存在)之原子質量或質量數之原子質量或質量數的原子置換或取代之本發明化合物。可併入本發明化合物中之合適放射性核素包括(但不限於)2 H(亦寫作D(氘))、3 H(亦寫作T(氚))、11 C、13 C、14 C、13 N、15 N、15 O、17 O、18 O、18 F、35 S、36 Cl、82 Br、75 Br、76 Br、77 Br、123 I、124 I、125 I及131 I。併入本發明之放射性標記化合物中之放射性核素將視該放射性標記化合物之特定應用而定。舉例而言，對於活體外IDO酶標記及競爭檢定，併有3 H、14 C、82 Br、125 I、131 I或35 S之化合物一般將最適用。對於放射性成像應用，11 C、18 F、125 I、123 I、124 I、131 I、75 Br、76 Br或77 Br一般將最適用。The invention further includes isotopically labeled compounds of formula I. An "isotopic" or "radiolabeled" compound is one in which one or more of the atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number normally present in the natural world (ie, naturally occurring). Compound. Suitable radionuclides which may be incorporated into the compounds of the invention include, but are not limited to, 2 H (also referred to as D(氘)), 3 H (also written as T(氚)), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I and 131 I. The radionuclide incorporated into the radiolabeled compound of the present invention will depend on the particular application of the radiolabeled compound. For example, compounds with 3 H, 14 C, 82 Br, 125 I, 131 I or 35 S will generally be most suitable for in vitro IDO enzyme labeling and competition assays. For radiographic applications, 11 C, 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br or 77 Br will generally be most suitable.

應理解「放射性標記」或「經標記化合物」為已併有至少一種放射性核素之化合物。在一些實施例中，放射性核素選自由3 H、14 C、125 I、35 S及82 Br組成之群。It should be understood that "radioactive label" or "labeled compound" is a compound that already has at least one radionuclide. In some embodiments, the radionuclide is selected from the group consisting of 3 H, 14 C, 125 I, 35 S, and 82 Br.

將放射性同位素併入有機化合物中之合成方法適用於本發明化合物且在此項技術中已熟知。Synthetic methods for incorporating radioisotopes into organic compounds are suitable for use in the compounds of the invention and are well known in the art.

本發明之放射性標記化合物可在篩檢檢定中用於鑑別/評估化合物。一般而言，可對新合成或鑑別之化合物(亦即測試化合物)評估其使本發明之放射性標記化合物與IDO酶結合減少的能力。因此，測試化合物與放射性標記化合物競爭結合IDO酶之能力與其結合親和力直接相關。The radiolabeled compounds of the invention can be used in screening assays to identify/evaluate compounds. In general, newly synthesized or identified compounds (i.e., test compounds) can be evaluated for their ability to reduce the binding of the radiolabeled compounds of the invention to IDO enzymes. Thus, the ability of a test compound to compete with a radiolabeled compound for binding to an IDO enzyme is directly related to its binding affinity.

套組Set

本發明亦包括適用於(例如)治療或預防與IDO相關性疾病或病症、肥胖症、糖尿病及本文中所提及之其他疾病之醫藥套組，其包括一或多個含有包含治療有效量之本發明化合物之醫藥組合物的容器。如對熟習此項技術者顯而易見，該等套組需要時可進一步包括一或多個不同的習知醫藥套組組件，諸如具有一或多種醫藥學上可接受之載劑的容器、其他容器等。套組中亦可包括指示待投與之組份之量、投與準則及/或用於使組份混合之準則的插頁或標記形式之說明書。The invention also includes a kit of medicines suitable for, for example, treating or preventing an IDO-associated disease or condition, obesity, diabetes, and other diseases mentioned herein, including one or more comprising a therapeutically effective amount A container for a pharmaceutical composition of a compound of the invention. As will be apparent to those skilled in the art, such kits may further include one or more different conventional medical kit components, such as containers having one or more pharmaceutically acceptable carriers, other containers, etc., as desired. . The kit may also include instructions in the form of an insert or mark indicating the amount of the component to be administered, the administration criteria, and/or the criteria for mixing the components.

本發明將藉助於特定實例更詳細地加以描述。提供以下實例以用於說明性目的，且並非意欲以任何方式來限制本發明。熟習此項技術者將易瞭解改變或修改多種非關鍵參數可產生基本上相同之結果。根據本文所提供之一或多種檢定，得知該等實例之化合物為IDO抑制劑。The invention will be described in more detail by means of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily appreciate that changing or modifying a plurality of non-critical parameters can produce substantially the same result. According to one or more assays provided herein, it is known that the compounds of these examples are IDO inhibitors.

實例Instance 實例1Example 1 4-({2-[(胺基磺醯基)胺基]乙基}胺基)- N -(3-溴-4-氟苯基)- N' -羥基-1,2,5- 二唑-3-甲醯亞胺醯胺 4 - ({2 - [(sulfo amino acyl) amino] ethyl} amino) - N - (3- bromo-4-fluorophenyl) - N '- hydroxy-1,2,5 Diazole-3-carboxamide

步驟A：4-胺基-N' -羥基-1,2,5-二唑-3-甲醯亞胺醯胺Step A: 4-Amino- N' -hydroxy-1,2,5- Diazole-3-carboxamide

向預先加熱至45℃之水(7 L)中添加丙二腈[Aldrich，產品號M1407](320.5 g，5 mol)且攪拌5分鐘。在冰浴中冷卻所得溶液且添加亞硝酸鈉(380 g，5.5 mol)。當溫度達到10℃時，添加6 N鹽酸(55 mL)。隨後發生輕度放熱反應，溫度達到16℃。15分鐘後，移除冷浴槽且將反應混合物在16-18℃下攪拌1.5小時。將反應混合物冷卻至13℃且一次性添加50%羥基胺水溶液(990 g，15 mol)。溫度升至26℃。當放熱反應減弱時，移除冷卻浴且在26-27℃下繼續攪拌1小時，接著使其緩慢地回流。保持回流2小時且接著使反應混合物冷卻隔夜。在冰浴中攪拌反應混合物且經40分鐘數份添加6 N鹽酸(800 mL)至pH 7.0。在冰浴中在5℃下繼續攪拌。藉由過濾收集沈澱物，以水充分洗滌且在真空烘箱(50℃)中乾燥以產生所要產物(644 g，90%)。C3 H6 N5 O2 (M+H)+ 之LCMS：m/z=144.0。13 C NMR(75 MHz,CD3 OD)：δ156.0,145.9,141.3。To a water (7 L) previously heated to 45 ° C, malononitrile [Aldrich, product No. M1407] (320.5 g, 5 mol) was added and stirred for 5 minutes. The resulting solution was cooled in an ice bath and sodium nitrite (380 g, 5.5 mol) was added. When the temperature reached 10 ° C, 6 N hydrochloric acid (55 mL) was added. A mild exothermic reaction then occurred and the temperature reached 16 °C. After 15 minutes, the cold bath was removed and the reaction mixture was stirred at 16-18 °C for 1.5 hours. The reaction mixture was cooled to 13 ° C and a 50% aqueous solution of hydroxylamine (990 g, 15 mol) was added in one portion. The temperature rose to 26 °C. When the exothermic reaction was weakened, the cooling bath was removed and stirring was continued at 26-27 ° C for 1 hour, then allowed to slowly reflux. The reflux was maintained for 2 hours and then the reaction mixture was allowed to cool overnight. The reaction mixture was stirred in an ice-bath and 6 N hydrochloric acid (800 mL) was then applied to pH 7.0. Stirring was continued at 5 ° C in an ice bath. The precipitate was collected by filtration, washed well with water and dried in a vacuum oven (50 ° C) to give the desired product (644 g, 90%). C 3 H 6 N 5 O 2 (M + H) + The LCMS: m / z = 144.0. 13 C NMR (75 MHz, CD 3 OD): δ 156.0, 145.9, 141.3.

步驟B：4-胺基-N -羥基-1,2,5-二唑-3-伸亞胺醯氯Step B: 4-Amino- N -hydroxy-1,2,5- Diazole-3-imine

向水(5.9 L)、乙酸(3 L)及6 N鹽酸(1.475 L，3當量)之混合物中添加4-胺基-N' -羥基-1,2,5-二唑-3-甲醯亞胺醯胺(422 g，2.95 mol)且在42-45℃下攪拌此懸浮液直至實現完全溶解。添加氯化鈉(518 g，3當量)且在冰/水/甲醇浴中攪拌此溶液。經3.5小時添加亞硝酸鈉(199.5 g，0.98當量)於水(700 mL)中之溶液，同時保持溫度低於0℃。添加完成後，在冰浴中繼續攪拌1.5小時且接著將反應混合物溫至15℃。藉由過濾收集沈澱物，以水充分洗滌，溶解於乙酸乙酯(3.4 L)中，以無水硫酸鈉(500 g)處理且攪拌1小時。經由硫酸鈉(200 g)過濾此懸浮液且在旋轉蒸發器上濃縮濾液。將殘餘物溶解於甲基第三丁基醚(5.5 L)中，以木炭(40 g)處理，攪拌40分鐘且經由矽藻土過濾。在旋轉蒸發器中移除溶劑，且在真空烘箱(45℃)中乾燥所得產物以產生所要產物(256 g，53.4%)。C3 H4 ClN4 O2 (M+H)+ 之LCMS：m/z=162.9。13 C NMR(100 MHz,CD3 OD)：δ155.8,143.4,129.7。Add 4-amino- N' -hydroxy-1,2,5- to a mixture of water (5.9 L), acetic acid (3 L) and 6 N hydrochloric acid (1.475 L, 3 eq.) The oxazol-3-carboxamimidamide (422 g, 2.95 mol) and the suspension was stirred at 42-45 °C until complete dissolution was achieved. Sodium chloride (518 g, 3 equivalents) was added and the solution was stirred in an ice/water/methanol bath. A solution of sodium nitrite (199.5 g, 0.98 equivalents) in water (700 mL) was added over 3.5 hours while maintaining the temperature below 0 °C. After the addition was completed, stirring was continued for 1.5 hours in an ice bath and then the reaction mixture was warmed to 15 °C. The precipitate was collected by filtration, washed with water, ethyl acetate (EtOAc) (EtOAc) The suspension was filtered through sodium sulphate (200 g) and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in methyl tributyl ether (5.5 L), taken up in charcoal (40 g), stirred for 40 min and filtered over Celite. The solvent was removed in a rotary evaporator and the resulting product was dried in a vacuum oven (45 ° C) to yield the desired product (256 g, 53.4%). C 3 H 4 ClN 4 O 2 (M + H) + The LCMS: m / z = 162.9. 13 C NMR (100 MHz, CD 3 OD): δ 155.8, 143.4, 129.7.

步驟C：4-胺基-N' -羥基-N -(2-甲氧基乙基)-1,2,5-二唑-3-甲醯亞胺醯胺Step C: 4-Amino- N' -hydroxy- N- (2-methoxyethyl)-1,2,5- Diazole-3-carboxamide

將4-胺基-N -羥基-1,2,5-二唑-3-甲醯亞胺醯氯(200.0 g，1.23 mol)與乙酸乙酯(1.2 L)混合。在0-5℃下，在攪拌下以一份添加2-甲氧基乙胺[Aldrich，產品號143693](119.0 mL，1.35 mol)。反應溫度升至41℃。將反應物冷卻至0-5℃。添加三乙胺(258 mL，1.84 mol)。攪拌5分鐘後，LCMS指示反應完成。以水(500 mL)及鹽水(500 mL)洗滌反應溶液，經硫酸鈉乾燥，且濃縮以產生呈暗黑色粗油狀之所要產物(294 g，119%)。C6 H12 N5 O3 (M+H)+ 之LCMS：m/z=202.3。1 H NMR(400 MHz,DMSO-d 6 )：δ10.65(s,1 H),6.27(s,2 H),6.10(t,J =6.5 Hz,1 H),3.50(m,2 H),3.35(d,J =5.8 Hz,2 H),3.08(s,3 H)。4-Amino- N -hydroxy-1,2,5- The oxazol-3-carboximine oxime chloride (200.0 g, 1.23 mol) was mixed with ethyl acetate (1.2 L). 2-Methoxyethylamine [Aldrich, product number 143693] (119.0 mL, 1.35 mol) was added in one portion with stirring at 0-5 °C. The reaction temperature rose to 41 °C. The reaction was cooled to 0-5 °C. Triethylamine (258 mL, 1.84 mol) was added. After stirring for 5 minutes, LCMS indicated the reaction was completed. The reaction solution was washed with EtOAc (EtOAc) (EtOAc) C 6 H 12 N 5 O 3 (M + H) + The LCMS: m / z = 202.3. 1 H NMR (400 MHz, DMSO- d 6 ): δ 10.65 (s, 1 H), 6.27 (s, 2 H), 6.10 (t, J = 6.5 Hz, 1 H), 3.50 (m, 2 H) ), 3.35 (d, J = 5.8 Hz, 2 H), 3.08 (s, 3 H).

步驟D：N' -羥基-4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯胺Step D: N' -hydroxy-4-[(2-methoxyethyl)amino]-1,2,5- Diazole-3-carboxamide

將4-胺基-N' -羥基-N -(2-甲氧基乙基)-1,2,5-二唑-3-甲醯亞胺醯胺(248.0 g，1.23 mol)與水(1 L)混合。添加氫氧化鉀(210 g，3.7 mol)。使反應物在100℃下回流隔夜(15小時)。使用己烷中之50%乙酸乙酯(含有1%氫氧化銨)之TLC指示反應完成(產物Rf=0.6，起始物質Rf=0.5)。LCMS亦指示反應完成。將反應物冷卻至室溫且以乙酸乙酯(3×1 L)萃取。經硫酸鈉乾燥經合併之乙酸乙酯溶液且濃縮以產生呈灰白色粗固體狀之所要產物(201 g，81%)。C6 H12 N5 O3 (M+H)+ 之LCMS：m/z=202.3。1 H NMR(400 MHz,DMSO-d 6 )：δ10.54(s,1 H),6.22(s,2 H),6.15(t,J =5.8 Hz,1 H),3.45(t,J =5.3 Hz,2 H),3.35(m,2 H),3.22(s,3 H)。4-Amino- N' -hydroxy- N- (2-methoxyethyl)-1,2,5- The oxazol-3-carboxamimidamide (248.0 g, 1.23 mol) was mixed with water (1 L). Potassium hydroxide (210 g, 3.7 mol) was added. The reaction was refluxed overnight (15 hours) at 100 °C. TLC using 50% ethyl acetate in hexanes (1% ammonium hydroxide) indicated the reaction was completed (product Rf = 0.6, starting material Rf = 0.5). LCMS also indicated that the reaction was complete. The reaction was cooled to room temperature and extracted with ethyl acetate (3×1 L). The combined ethyl acetate solution was dried with EtOAc (EtOAc m. C 6 H 12 N 5 O 3 (M + H) + The LCMS: m / z = 202.3. 1 H NMR (400 MHz, DMSO- d 6 ): δ 10.54 (s, 1 H), 6.22 (s, 2 H), 6.15 (t, J = 5.8 Hz, 1 H), 3.45 (t, J = 5.3 Hz, 2 H), 3.35 (m, 2 H), 3.22 (s, 3 H).

步驟E：N -羥基-4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯氯Step E: N -Hydroxy-4-[(2-methoxyethyl)amino]-1,2,5- Diazole-3-carboximine

在室溫下，將N' -羥基-4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯胺(50.0 g，0.226 mol)溶解於6.0 M鹽酸水溶液(250 mL，1.5 mol)中。添加氯化鈉(39.5 g，0.676 mol)，隨後添加水(250 mL)及乙酸乙酯(250 mL)。在3-5℃下，經1小時緩慢添加預先製備之亞硝酸鈉(15.0 g，0.217 mol)水溶液(100 mL)。將反應物在3-8℃下攪拌2小時，且接著在室溫下攪拌整個週末。LCMS指示反應完成。以乙酸乙酯(2×200 mL)萃取反應溶液。經硫酸鈉乾燥經合併之乙酸乙酯溶液且濃縮以產生呈白色粗固體狀之所要產物(49.9 g，126%)。C6 H10 ClN4 O3 (M+H)+ 之LCMS：m/z=221.0。1 H NMR(400 MHz,DMSO-d 6 )：δ13.43(s,1 H),5.85(t,J =5.6 Hz,1 H),3.50(t,J =5.6 Hz,2 H),3.37(dd,J =10.8,5.6 Hz,2 H),3.25(s,3 H)。 N' -hydroxy-4-[(2-methoxyethyl)amino]-1,2,5- at room temperature The oxazol-3-carboxamimidamide (50.0 g, 0.226 mol) was dissolved in 6.0 M aqueous hydrochloric acid (250 mL, 1.5 mol). Sodium chloride (39.5 g, 0.676 mol) was added followed by water (250 mL) and ethyl acetate (250 mL). A pre-prepared aqueous solution of sodium nitrite (15.0 g, 0.217 mol) (100 mL) was slowly added over 1 hour at 3-5 °C. The reaction was stirred at 3-8 °C for 2 hours and then stirred at room temperature over the weekend. LCMS indicated the reaction was complete. The reaction solution was extracted with ethyl acetate (2×200 mL). The combined ethyl acetate solution was dried <RTI ID=0.0> C 6 H 10 ClN 4 O 3 (M + H) + The LCMS: m / z = 221.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 13.43 (s, 1 H), 5.85 (t, J = 5.6 Hz, 1 H), 3.50 (t, J = 5.6 Hz, 2 H), 3.37 (dd, J = 10.8, 5.6 Hz, 2 H), 3.25 (s, 3 H).

步驟F：N -(3-溴-4-氟苯基)-N' -羥基-4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯胺Step F: N - (3- bromo-4-fluorophenyl) - N '- hydroxy-4 - [(2-methoxyethyl) amino] -1,2,5 Diazole-3-carboxamide

將N -羥基-4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯氯(46.0 g，0.208 mol)與水(300 mL)混合。將混合物加熱至60℃。添加3-溴-4-氟苯胺[Oakwood products，產品號013091](43.6 g，0.229 mol)且攪拌10分鐘。經15分鐘添加溫碳酸氫鈉(26.3 g，0.313 mol)溶液(300 mL水)。將反應物在60℃下攪拌20分鐘。LCMS指示反應完成。將反應溶液冷卻至室溫且以乙酸乙酯(2×300 mL)萃取。經硫酸鈉乾燥經合併之乙酸乙酯溶液且濃縮以產生呈棕色粗固體狀之所要產物(76.7 g，98%)。C12 H14 BrFN5 O3 (M+H)+ 之LCMS：m/z=374.0,376.0。1 H NMR(400 MHz,DMSO-d 6 )：δ11.55(s,1 H),8.85(s,1 H),7.16(t,J =8.8 Hz,1 H),7.08(dd,J =6.1,2.7 Hz,1 H),6.75(m,1 H),6.14(t,J =5.8 Hz,1 H),3.48(t,J =5.2 Hz,2 H),3.35(dd,J =10.8,5.6 Hz,2 H),3.22(s,3 H)。 N -hydroxy-4-[(2-methoxyethyl)amino]-1,2,5- The oxazol-3-carboximine oxime chloride (46.0 g, 0.208 mol) was mixed with water (300 mL). The mixture was heated to 60 °C. 3-Bromo-4-fluoroaniline [Oakwood products, product number 013091] (43.6 g, 0.229 mol) was added and stirred for 10 minutes. A solution of warm sodium bicarbonate (26.3 g, 0.313 mol) (300 mL water) was added over 15 minutes. The reaction was stirred at 60 ° C for 20 minutes. LCMS indicated the reaction was complete. The reaction solution was cooled to room temperature and extracted with ethyl acetate (2×300 mL). The combined ethyl acetate solution was dried <RTI ID=0.0> C 12 H 14 BrFN 5 O 3 (M + H) + The LCMS: m / z = 374.0,376.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 11.55 (s, 1 H), 8.85 (s, 1 H), 7.16 (t, J = 8.8 Hz, 1 H), 7.08 (dd, J = 6.1, 2.7 Hz, 1 H), 6.75 (m, 1 H), 6.14 (t, J = 5.8 Hz, 1 H), 3.48 (t, J = 5.2 Hz, 2 H), 3.35 (dd, J = 10.8) , 5.6 Hz, 2 H), 3.22 (s, 3 H).

步驟G：4-(3-溴-4-氟苯基)-3-{4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H )-酮Step G: 4-(3-Bromo-4-fluorophenyl)-3-{4-[(2-methoxyethyl)amino]-1,2,5- Diazol-3-yl}-1,2,4- Diazol-5(4 H )-one

將N -(3-溴-4-氟苯基)-N' -羥基-4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯胺(76.5 g，0.204 mol)、1,1'-羰基二咪唑(49.7 g，0.307 mol)與乙酸乙酯(720 mL)之混合物加熱至60℃且攪拌20分鐘。LCMS指示反應完成。將反應物冷卻至室溫，以1 N HCl(2×750 mL)洗滌，經硫酸鈉乾燥，且濃縮以產生呈棕色粗固體狀之所要產物(80.4 g，98%)。C13 H12 BrFN5 O4 (M+H)+ 之LCMS：m/z=400.0,402.0。1 H NMR(400 MHz,DMSO-d 6 )：δ7.94(t,J =8.2 Hz,1 H),7.72(dd,J =9.1,2.3 Hz,1 H),7.42(m,1 H),6.42(t,J =5.7 Hz,1 H),3.46(t,J =5.4 Hz,2 H),3.36(t,J =5.8 Hz,2 H),3.26(s,3 H)。The N - (3- bromo-4-fluorophenyl) - N '- hydroxy-4 - [(2-methoxyethyl) amino] -1,2,5 A mixture of oxazol-3-carboxamimidamide (76.5 g, 0.204 mol), 1,1'-carbonyldiimidazole (49.7 g, 0.307 mol) and ethyl acetate (720 mL) was heated to 60 ° C and stirred. 20 minutes. LCMS indicated the reaction was complete. The reaction was cooled to rt EtOAc (EtOAc)EtOAc. C 13 H 12 BrFN 5 O 4 (M + H) + The LCMS: m / z = 400.0,402.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 7.94 (t, J = 8.2 Hz, 1 H), 7.72 (dd, J = 9.1, 2.3 Hz, 1 H), 7.42 (m, 1 H) , 6.42 (t, J = 5.7 Hz, 1 H), 3.46 (t, J = 5.4 Hz, 2 H), 3.36 (t, J = 5.8 Hz, 2 H), 3.26 (s, 3 H).

步驟H：4-(3-溴-4-氟苯基)-3-{4-[(2-羥基乙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H )-酮Step H: 4-(3-Bromo-4-fluorophenyl)-3-{4-[(2-hydroxyethyl)amino]-1,2,5- Diazol-3-yl}-1,2,4- Diazol-5(4 H )-one

將4-(3-溴-4-氟苯基)-3-{4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H )-酮(78.4 g，0.196 mol)溶解於二氯甲烷(600 mL)中。在-67℃下，經15分鐘添加三溴化硼(37 mL，0.392 mol)。將反應物在30分鐘內溫至-10℃。LCMS指示反應完成。將反應物在室溫下攪拌1小時。在0-5℃下，以碳酸氫鈉飽和溶液(1.5 L)經30分鐘緩慢中止反應。反應溫度升至25℃。以乙酸乙酯萃取反應物(2×500 mL，第一萃取有機層位於底部且第二萃取有機層位於頂部)。經硫酸鈉乾燥經合併之有機層且濃縮以產生呈棕色粗固體狀之所要產物(75 g，99%)。C12 H10 BrFN5 O4 (M+H)+ 之LCMS：m/z=386.0,388.0。1 H NMR(400 MHz,DMSO-d 6 )：δ8.08(dd,J =6.2,2.5 Hz,1 H),7.70(m,1 H),7.68(t,J =8.7 Hz,1 H),6.33(t,J =5.6 Hz,1 H),4.85(t,J =5.0 Hz,1 H),3.56(dd,J =10.6,5.6 Hz,2 H),3.29(dd,J =11.5,5.9 Hz,2 H)。4-(3-Bromo-4-fluorophenyl)-3-{4-[(2-methoxyethyl)amino]-1,2,5- Diazol-3-yl}-1,2,4- The oxazol-5( 4H )-one (78.4 g, 0.196 mol) was dissolved in dichloromethane (600 mL). Boron tribromide (37 mL, 0.392 mol) was added over 15 minutes at -67 °C. The reaction was warmed to -10 °C over 30 minutes. LCMS indicated the reaction was complete. The reaction was stirred at room temperature for 1 hour. The reaction was slowly quenched with a saturated solution of sodium bicarbonate (1.5 L) at 0-5 ° C over 30 min. The reaction temperature was raised to 25 °C. The reaction was extracted with ethyl acetate (2 x 500 mL, the first extracted organic layer was at the bottom and the second extracted organic layer was at the top). The combined organic layers were dried with EtOAc (EtOAc m. C 12 H 10 BrFN 5 O 4 (M + H) + The LCMS: m / z = 386.0,388.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.08 (dd, J = 6.2, 2.5 Hz, 1 H), 7.70 (m, 1 H), 7.68 (t, J = 8.7 Hz, 1 H) , 6.33 (t, J = 5.6 Hz, 1 H), 4.85 (t, J = 5.0 Hz, 1 H), 3.56 (dd, J = 10.6, 5.6 Hz, 2 H), 3.29 (dd, J =11.5, 5.9 Hz, 2 H).

步驟I：甲烷磺酸2-({4-[4-(3-溴-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}胺基)乙酯Step I: 2-({4-[4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4- methanesulfonic acid) Diazol-3-yl]-1,2,5- Diazol-3-yl}amino)ethyl ester

在室溫下經1小時向4-(3-溴-4-氟苯基)-3-{4-[(2-羥基乙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H )-酮(1.5 kg，3.9 mol，亦含有一些相應溴化合物)於乙酸乙酯(12 L)中之溶液中逐滴添加甲烷磺醯氯(185 mL，2.4 mol)。經45分鐘逐滴添加三乙胺(325 mL，2.3 mol)，在此期間反應溫度增至35℃。2小時後，以水(5 L)、鹽水(1 L)洗滌反應混合物，經硫酸鈉乾燥，與另外3份相同量之反應物合併，且真空移除溶劑以產生呈棕褐色固體狀之所要產物(7600 g，定量產量)。C13 H11 BrFN5 O6 SNa(M+Na)+ 之LCMS：m/z=485.9,487.9。1 H NMR(400 MHz,DMSO-d 6 )：68.08(dd,J =6.2,2.5 Hz,1 H),7.72(m,1 H),7.58(t,J =8.7 Hz,1 H),6.75(t,J =5.9 Hz,1 H),4.36(t,J =5.3 Hz,2 H),3.58(dd,J =11.2,5.6 Hz,2 H),3.18(s,3 H)。To 4-(3-bromo-4-fluorophenyl)-3-{4-[(2-hydroxyethyl)amino]-1,2,5- at room temperature over 1 hour Diazol-3-yl}-1,2,4- Methanesulfonium chloride (185 mL, 2.4 mol) was added dropwise to a solution of oxazol-5( 4H )-one (1.5 kg, 3.9 mol, also containing some corresponding bromine compound) in ethyl acetate (12 L) . Triethylamine (325 mL, 2.3 mol) was added dropwise over 45 minutes, during which time the reaction temperature was increased to 35 °C. After 2 hours, the reaction mixture was washed with water (5 L), brine (1 L), dried over sodium sulfate and combined with three additional portions of the mixture, and the solvent was removed in vacuo to give a brown solid. Product (7600 g, quantitative yield). C 13 H 11 BrFN 5 O 6 SNa (M + Na) + The LCMS: m / z = 485.9,487.9. 1 H NMR (400 MHz, DMSO- d 6 ): 68.08 (dd, J = 6.2, 2.5 Hz, 1 H), 7.72 (m, 1 H), 7.58 (t, J = 8.7 Hz, 1 H), 6.75 (t, J = 5.9 Hz, 1 H), 4.36 (t, J = 5.3 Hz, 2 H), 3.58 (dd, J = 11.2, 5.6 Hz, 2 H), 3.18 (s, 3 H).

步驟J：3-{4-[(2-疊氮基乙基)胺基]-1,2,5-二唑-3-基}-4-(3-溴-4-氟苯基)-1,2,4-二唑-5(4H )-酮Step J: 3-{4-[(2-azidoethyl)amino]-1,2,5- Diazol-3-yl}-4-(3-bromo-4-fluorophenyl)-1,2,4- Diazol-5(4 H )-one

向在22 L燒瓶中攪拌之甲烷磺酸2-({4-[4-(3-溴-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}胺基)乙酯(2.13 kg，4.6 mol，亦含有一些相應溴化合物)於二甲基甲醯胺(4 L)中之溶液中添加疊氮化鈉(380 g，5.84 mol)。將反應物在50℃下加熱6小時，傾注於冰/水(8 L)中，且以1：1乙酸乙酯：庚烷(20 L)萃取。以水(5 L)及鹽水(5 L)洗滌有機層，且真空移除溶劑以產生呈棕褐色固體狀之所要產物(1464 g，77%)。C12 H8 BrFN8 O3 Na(M+Na)+ 之LCMS：m/z=433.0,435.0。1 H NMR(400 MHz,DMSO-d 6 )：δ8.08(dd,J =6.2,2.5 Hz,1 H),7.72(m,1 H),7.58(t,J =8.7 Hz,1 H),6.75(t,J =5.7 Hz,1 H),3.54(t,J =5.3 Hz,2 H),3.45(dd,J =11.1,5.2 Hz,2 H)。2-({4-[4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4 methanesulfonate) stirred in a 22 L flask - Diazol-3-yl]-1,2,5- Adding sodium azide (380 g, oxazol-3-yl}amino)ethyl ester (2.13 kg, 4.6 mol, also containing some corresponding bromine compound) in dimethylformamide (4 L) 5.84 mol). The reaction was heated at 50 &lt;0&gt;C for 6 h, poured over ice/water (8L) andEtOAcEtOAc The organic layer was washed with EtOAc (EtOAc)EtOAc. C 12 H 8 BrFN 8 O 3 Na (M + Na) + The LCMS: m / z = 433.0,435.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.08 (dd, J = 6.2, 2.5 Hz, 1 H), 7.72 (m, 1 H), 7.58 (t, J = 8.7 Hz, 1 H) , 6.75 (t, J = 5.7 Hz, 1 H), 3.54 (t, J = 5.3 Hz, 2 H), 3.45 (dd, J = 11.1, 5.2 Hz, 2 H).

步驟K：3-{4-[(2-胺基乙基)胺基]-1,2,5-二唑-3-基}-4-(3-溴-4-氟苯基)-1,2,4-二唑-5(4H )-酮鹽酸鹽Step K: 3-{4-[(2-Aminoethyl)amino]-1,2,5- Diazol-3-yl}-4-(3-bromo-4-fluorophenyl)-1,2,4- Diazol-5(4 H )-one hydrochloride

向甲醇(6 L)中之3-{4-[(2-疊氮基乙基)胺基]-1,2,5-二唑-3-基}-4-(3-溴-4-氟苯基)-1,2,4-二唑-5(4H )-酮(500 g，1.22 mol)中添加碘化鈉(1080 g，7.2 mol)。將混合物攪拌30分鐘，此期間觀測到輕度放熱。以使得溫度不超過35℃之速率、以甲醇(1 L)中之溶液的形式逐滴添加氯三甲基矽烷(930 mL，7.33 mol)，且將反應物在環境溫度下攪拌3.5小時。以五水合硫代硫酸鈉於水(約1.5 L)中之33重量%溶液中和反應物，以水(4 L)稀釋且以固體碳酸鉀(250 g，以小份添加：注意發泡)小心地將pH值調整至9。添加二碳酸二-第三丁酯(318 g，1.45 mol)且在室溫下攪拌反應物。經4小時以50 g數份添加額外碳酸鉀(200 g)以確保pH值仍為9或高於9。在室溫下攪拌隔夜後，過濾固體，以水(2 L)濕磨，且接著以MTBE(1.5 L)濕磨。總共進行11輪處理(5.5 kg，13.38 mol)。以1：1 THF：二氯甲烷(24 L，在20 L旋轉蒸發器燒瓶中進行4輪處理，50℃，1小時)濕磨經合併之固體，過濾且以二氯甲烷(每輪3 L)洗滌以產生灰白色固體。在55℃下將粗物質溶解於四氫呋喃(5 mL/g)中，以脫色碳(2重量%)及矽膠(2重量%)處理，經由矽藻土熱過濾以產生呈灰白色固體狀之產物(5122 g)。真空濃縮經合併之MTBE、THF及二氯甲烷濾液且層析(2 kg矽膠，具有0-100%乙酸乙酯梯度之庚烷，30 L)，以產生更多產物(262 g)。在對流烘箱中將經合併固體乾燥至恆重(5385 g，83%)。3-{4-[(2-azidoethyl)amino]-1,2,5- to methanol (6 L) Diazol-3-yl}-4-(3-bromo-4-fluorophenyl)-1,2,4- Sodium iodide (1080 g, 7.2 mol) was added to the oxazol-5( 4H )-one (500 g, 1.22 mol). The mixture was stirred for 30 minutes during which a slight exotherm was observed. Chlorotrimethylnonane (930 mL, 7.33 mol) was added dropwise in the form of a solution in methanol (1 L) at a rate such that the temperature did not exceed 35 ° C, and the reaction was stirred at ambient temperature for 3.5 hours. The reaction was neutralized with a 33% by weight solution of sodium thiosulfate pentahydrate in water (about 1.5 L), diluted with water (4 L) and solid potassium carbonate (250 g, added in small portions: note foaming) Carefully adjust the pH to 9. Di-tert-butyl dicarbonate (318 g, 1.45 mol) was added and the reaction was stirred at room temperature. Additional potassium carbonate (200 g) was added in 50 g portions over 4 hours to ensure that the pH was still 9 or above 9. After stirring overnight at room temperature, the solid was filtered, wet-purified with water (2L), and then wet-milled with MTBE (1.5 L). A total of 11 rounds of treatment (5.5 kg, 13.38 mol) were performed. The combined solids were wet-milled in 1:1 THF: dichloromethane (24 L, 4 rounds in a 20 L rotary evaporator flask, 50 ° C, 1 hour), filtered and taken in dichloromethane (3 L per round) Wash to produce an off-white solid. The crude material was dissolved in tetrahydrofuran (5 mL/g) at 55 ° C, treated with decoloring carbon (2% by weight) and silica gel (2% by weight), and filtered through celite to give a product as an off-white solid ( 5122 g). The combined MTBE, THF and dichloromethane filtrates were concentrated in vacuo and chromatographed (2 g EtOAc EtOAc EtOAc EtOAc The combined solids were dried to constant weight (5385 g, 83%) in a convection oven.

將氯化氫(1,4-二烷中之4 N溶液，4 L，16 mol)饋入22 L燒瓶中。經10分鐘以固體形式數份添加[2-({4-[4-(3-溴-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}胺基)乙基]胺基甲酸第三丁酯(2315 g，4.77 mol)。在室溫下攪拌漿液且逐漸變為不能攪拌之黏稠糊狀物。在室溫下攪拌隔夜後，將糊狀物在乙酸乙酯(10 L)中製成漿液，過濾，在乙酸乙酯(5 L)中再製成漿液，過濾且乾燥至恆重以產生呈白色固體狀之所要產物(與其他處理合併，饋入5 kg起始物質，4113 g，95%)。C12 H11 BrFN6 O3 (M+H)+ 之LCMS：m/z=384.9,386.9。1 H NMR(400 MHz,DMSO-d 6 )：δ8.12(m,4 H),7.76(m,1 H),7.58(t,J =8.7 Hz,1 H),6.78(t,J =6.1 Hz,1 H),3.51(dd,J =11.8,6.1 Hz,2 H),3.02(m,2 H)。Hydrogen chloride (1,4-di The 4 N solution in the alkane, 4 L, 16 mol) was fed into a 22 L flask. [2-({4-[4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-) was added in several portions as a solid over 10 min. Diazol-3-yl]-1,2,5- Tert-butyl 3-oxazol-3-yl}amino)ethyl]carbamic acid (2315 g, 4.77 mol). The slurry was stirred at room temperature and gradually became a viscous paste that could not be stirred. After stirring overnight at room temperature, the syrup was slurried in ethyl acetate (10 L), filtered, and then resed in ethyl acetate (5 L), filtered and dried to constant weight to yield The desired product was obtained as a white solid ( combined with other treatments, 5 kg starting material, 4113 g, 95%). C 12 H 11 BrFN 6 O 3 (M + H) + The LCMS: m / z = 384.9,386.9. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.12 (m, 4 H), 7.76 (m, 1 H), 7.58 (t, J = 8.7 Hz, 1 H), 6.78 (t, J = 6.1 Hz, 1 H), 3.51 (dd, J = 11.8, 6.1 Hz, 2 H), 3.02 (m, 2 H).

步驟L：({[2-({4-[4-(3-溴-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}胺基)乙基]胺基}磺醯基)胺基甲酸第三丁酯Step L: ({[2-({4-[4-(3-Bromo-4-fluorophenyl)-5- pendantoxy-4,5-dihydro-1,2,4- Diazol-3-yl]-1,2,5- Diazol-3-yl}amino)ethyl]amino}sulfonyl) carboxylic acid tert-butyl ester

將氯磺醯異氰酸酯[Aldrich，產品號142662](149 mL，1.72 mol)及二氯甲烷(1.5 L)饋入5 L圓底燒瓶中且使用冰浴冷卻至2℃。以使得溫度不超過10℃之速率逐滴添加二氯甲烷(200 mL)中之第三丁醇(162 mL，1.73 mol)。將所得溶液在室溫下攪拌30-60分鐘以產生[氯磺醯基]胺基甲酸第三丁酯。Chlorosulfonium isocyanate [Aldrich, product number 142662] (149 mL, 1.72 mol) and dichloromethane (1.5 L) were fed to a 5 L round bottom flask and cooled to 2 ° C using an ice bath. The third butanol (162 mL, 1.73 mol) in dichloromethane (200 mL) was added dropwise at a rate such that the temperature did not exceed 10 °C. The resulting solution was stirred at room temperature for 30-60 minutes to give [chlorosulfonyl] carbamic acid tert-butyl ester.

將3-{4-[(2-胺基乙基)胺基]-1,2,5-二唑-3-基}-4-(3-溴-4-氟苯基)-1,2,4-二唑-5(4H )-酮鹽酸鹽(661 g，1.57 mol)及8.5 L二氯甲烷饋入22 L燒瓶中。以冰/鹽浴冷卻至-15℃之後，以使得溫度不超過-10℃之速率添加[氯磺醯基]胺基甲酸第三丁酯溶液(如上文所述製備)(添加時間7分鐘)。攪拌10分鐘後，以使得溫度不超過-5℃之速率添加三乙胺(1085 mL，7.78 mol)(添加時間10分鐘)。移除冷卻浴，使反應物溫至10℃，分成兩份，且以10%濃鹽酸(每份4.5 L)中和。將各份轉移至50 L分液漏斗中且以乙酸乙酯稀釋以完全溶解白色固體(約25 L)。分離各層，且以水(5 L)、鹽水(5 L)洗滌各層且真空移除溶劑以產生灰白色固體。以MTBE(2×1.5 L)濕磨固體且乾燥至恆重以產生白色固體。以此方式處理總共4113 g起始物質(5409 g，98%)。1 H NMR(400 MHz,DMSO-d 6 )：δ10.90(s,1 H),8.08(dd,J =6.2,2.5 Hz,1 H),7.72(m,1 H),7.59(t,J =8.6 Hz,1 H),6.58(t,J =5.7 Hz,1 H),3.38(dd,J =12.7,6.2 Hz,2 H),3.10(dd,J =12.1,5.9 Hz,2 H),1.41(s,9 H)。3-{4-[(2-Aminoethyl)amino]-1,2,5- Diazol-3-yl}-4-(3-bromo-4-fluorophenyl)-1,2,4- The oxazol-5( 4H )-one hydrochloride (661 g, 1.57 mol) and 8.5 L of dichloromethane were fed into a 22 L flask. After cooling to -15 ° C in an ice/salt bath, a solution of [chlorosulfonyl] carbamic acid tert-butyl ester (prepared as described above) was added at a rate such that the temperature did not exceed -10 ° C (addition time 7 minutes) . After stirring for 10 minutes, triethylamine (1085 mL, 7.78 mol) was added at a rate such that the temperature did not exceed -5 ° C (addition time 10 minutes). The cooling bath was removed and the reaction was warmed to 10 ° C, taken in two portions and neutralized with 10% concentrated hydrochloric acid (4.5 L each). The fractions were transferred to a 50 L separatory funnel and diluted with ethyl acetate to dissolve a white solid (~25L). The layers were separated and the layers were washed with water (5 L), brine (5L) and solvent was evaporated in vacuo. The solid was wet milled with MTBE (2 x 1.5 L) and dried to constant weight to give a white solid. A total of 4113 g of starting material (5409 g, 98%) was treated in this way. 1 H NMR (400 MHz, DMSO- d 6 ): δ 10.90 (s, 1 H), 8.08 (dd, J = 6.2, 2.5 Hz, 1 H), 7.72 (m, 1 H), 7.59 (t, J = 8.6 Hz, 1 H), 6.58 (t, J = 5.7 Hz, 1 H), 3.38 (dd, J = 12.7, 6.2 Hz, 2 H), 3.10 (dd, J = 12.1, 5.9 Hz, 2 H ), 1.41 (s, 9 H).

步驟M：N -[2-({4-[4-(3-溴-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}胺基)乙基]磺醯胺Step M: N -[2-({4-[4-(3-Bromo-4-fluorophenyl)-5-yloxy-4,5-dihydro-1,2,4- Diazol-3-yl]-1,2,5- Diazol-3-yl}amino)ethyl]sulfonamide

經10分鐘向含有98：2之三氟乙酸：水(8.9 L)之22 L燒瓶中數份添加({[2-({4-[4-(3-溴-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}胺基)乙基]胺基}磺醯基)胺基甲酸第三丁酯(1931 g，3.42 mol)。將所得混合物在室溫下攪拌1.5小時，真空移除溶劑且追加二氯甲烷(2 L)。再次以新鮮98：2三氟乙酸：水(8.9 L)處理所得固體，在40-50℃下加熱1小時，真空移除溶劑且追加二氯甲烷(3×2 L)。在真空乾燥烘箱中、在50℃下乾燥所得白色固體隔夜。以此方式總共處理5409 g(4990 g，定量產量)。C12 H12 BrFN7 O5 S(M+H)+ 之LCMS：m/z=463.9,465.9。1 H NMR(400 MHz,DMSO-d 6 )：δ8.08(dd,J =6.2,2.5 Hz,1 H),7.72(m,1 H),7.59(t,J =8.7 Hz,1 H),6.67(t,J =5.9 Hz,1H),6.52(t,J =6.0 Hz,1 H),3.38(dd,J =12.7,6.3 Hz,2 H),3.11(dd,J =12.3,6.3 Hz)。({[2-({4-[4-(3-Bromo-4-fluorophenyl))) was added in several portions to a 22 L flask containing 98:2 trifluoroacetic acid: water (8.9 L) over 10 min. 5-sided oxy-4,5-dihydro-1,2,4- Diazol-3-yl]-1,2,5- Diazol-3-yl}amino)ethyl]amino}sulfonyl) carbamic acid tert-butyl ester (1931 g, 3.42 mol). The resulting mixture was stirred at room temperature for 1.5 hr. The resulting solid was treated again with fresh 98:2 trifluoroacetic acid: water (8.9L), mp. The resulting white solid was dried overnight at 50 ° C in a vacuum drying oven. A total of 5409 g (4990 g, quantitative yield) was processed in this way. C 12 H 12 BrFN 7 O 5 S (M + H) + The LCMS: m / z = 463.9,465.9. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.08 (dd, J = 6.2, 2.5 Hz, 1 H), 7.72 (m, 1 H), 7.59 (t, J = 8.7 Hz, 1 H) , 6.67 (t, J = 5.9 Hz, 1H), 6.52 (t, J = 6.0 Hz, 1 H), 3.38 (dd, J = 12.7, 6.3 Hz, 2 H), 3.11 (dd, J = 12.3, 6.3 Hz).

步驟N：4-({2-[(胺基磺醯基)胺基]乙基}胺基)-N -(3-溴-4-氟苯基)-N' -羥基-1,2,5-二唑-3-甲醯亞胺醯胺Step N: 4 - ({2 - [( sulfo amino acyl) amino] ethyl} amino) - N - (3- bromo-4-fluorophenyl) - N '- hydroxy-1,2, 5- Diazole-3-carboxamide

向在22 L燒瓶中攪拌之含有殘餘量之三氟乙酸的N -[2-({4-[4-(3-溴-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}胺基)乙基]磺醯胺(2.4 mol)之粗混合物中添加THF(5 L)。使用冰浴將所得溶液冷卻至0℃且以使得溫度不超過10℃之速率添加2 N NaOH(4 L)。在環境溫度下攪拌3小時之後(LCMS指示無剩餘之起始物質)，以濃鹽酸(約500 mL)將pH值調整至3-4。真空移除THF，且以乙酸乙酯(15 L)萃取所得混合物。以水(5 L)、鹽水(5 L)洗滌有機層，且真空移除溶劑以產生固體。以MTBE(2×2 L)濕磨固體，與另外三份相同量之反應物合併，且在對流烘箱中乾燥隔夜以產生白色固體(3535 g)。將固體再結晶(3×22 L燒瓶，2：1水：乙醇，每個燒瓶14.1 L)且在50℃對流烘箱中乾燥至恆重以產生呈灰白色固體狀之標題化合物(3290 g，78%)。C11 H14 BrFN7 O4 S(M+H)+ 之LCMS：m/z=437.9,439.9。1 H NMR(400 MHz,DMSO-d 6 )：δ11.51(s,1 H),8.90(s,1 H),7.17(t,J =8.8 Hz,1 H),7.11(dd,J =6.1,2.7 Hz,1 H),6.76(m,1 H),6.71(t,J =6.0 Hz,1 H),6.59(s,2 H),6.23(t,J =6.1 Hz,1 H),3.35(dd,J =10.9,7.0 Hz,2 H),3.10(dd,J =12.1,6.2 Hz,2 H)。 N- [2-({4-[4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-) containing a residual amount of trifluoroacetic acid in a 22 L flask. Dihydro-1,2,4- Diazol-3-yl]-1,2,5- To the crude mixture of oxazol-3-yl}amino)ethyl]sulfonamide (2.4 mol) was added THF (5 L). The resulting solution was cooled to 0 °C using an ice bath and 2 N NaOH (4 L) was added at such a rate that the temperature did not exceed 10 °C. After stirring at ambient temperature for 3 hours (LCMS indicated no starting material remaining), the pH was adjusted to 3-4 with concentrated hydrochloric acid (approximately 500 mL). The THF was removed in vacuo and the mixture was extracted with ethyl acetate (15L). The organic layer was washed with water (5 L), brine (5 L) and solvent was evaporated in vacuo to give a solid. The solid was wet milled with MTBE (2 x 2 L), combined with three additional portions of the mixture and dried overnight in a convection oven to yield a white solid (3535 g). The solid was recrystallized (3 x 22 L flasks, 2:1 water: EtOAc, EtOAc: EtOAc) ). C 11 H 14 BrFN 7 O 4 S (M + H) + The LCMS: m / z = 437.9,439.9. 1 H NMR (400 MHz, DMSO- d 6 ): δ 11.51 (s, 1 H), 8.90 (s, 1 H), 7.17 (t, J = 8.8 Hz, 1 H), 7.11 (dd, J = 6.1, 2.7 Hz, 1 H), 6.76 (m, 1 H), 6.71 (t, J = 6.0 Hz, 1 H), 6.59 (s, 2 H), 6.23 (t, J = 6.1 Hz, 1 H) , 3.35 (dd, J = 10.9, 7.0 Hz, 2 H), 3.10 (dd, J = 12.1, 6.2 Hz, 2 H).

最終產物為無水結晶固體。藉由Karl Fischer滴定測得水含量低於0.1%。測定X射線粉末繞射(XRPD)圖(Rigaku MiniFlex粉末繞射儀；Cu，1.054056，使用Kβ過濾器；起始角=3，終止角=45，取樣=0.02，掃描速度=2)且展示於圖1中。下表1中提供2θ峰值之清單。在Mettler Toledo差示掃描熱量測定(DSC)822儀器上測定固體之熔融範圍。以10℃/min之加熱速率將樣本自40℃加熱至240℃。DSC熱分析圖(圖2)展示162.7℃之Tonset 及163.8℃之Tpeak 。熱解重量分析(TGA)(圖3)展示0.3%之重量損失，其使用TA Instrument Q500、以10℃/min之加熱速率自20℃加熱至150℃。The final product was an anhydrous crystalline solid. The water content was determined to be less than 0.1% by Karl Fischer titration. Determination of X-ray powder diffraction (XRPD) diagram (Rigaku MiniFlex powder diffraction instrument; Cu, 1.054056 Using a Kβ filter; starting angle = 3, ending angle = 45, sampling = 0.02, scanning speed = 2) and shown in Figure 1. A list of 2θ peaks is provided in Table 1 below. The melting range of the solids was determined on a Mettler Toledo Differential Scanning Calorimetry (DSC) 822 instrument. The sample was heated from 40 ° C to 240 ° C at a heating rate of 10 ° C / min. DSC thermogram (FIG. 2) shows a T onset 162.7 ℃ and of the T peak 163.8 ℃. Thermogravimetric analysis (TGA) (Figure 3) exhibited a weight loss of 0.3%, which was heated from 20 °C to 150 °C using a TA Instrument Q500 at a heating rate of 10 °C/min.

實例2Example 2 N -(3-溴-4-氟苯基)- N' -羥基-4-({2-[(甲基磺醯基)胺基]乙基}胺基)-1,2,5- 二唑-3-甲醯亞胺醯胺 N - (3- bromo-4-fluorophenyl) - N '- hydroxy-4 - ({2 - [(acyl sulfo methyl) amino] ethyl} amino) -1,2,5 Diazole-3-carboxamide

使用N '-羥基-4-({2-[(甲基磺醯基)胺基]乙基}胺基)-1,2,5-二唑-3-甲醯亞胺醯胺及3-溴-4-氟苯胺[Oakwood Products,Inc.，產品號013091]作為起始物質、根據實例17步驟E 之程序製備標題化合物。C12 H15 BrFN6 O4 S(M+H)+ 之LCMS：m/z=437.0,439.0。1 H NMR(400 MHz,DMSO-d 6 )：δ11.49(s,1H),8.90(s,1H),7.17(m,2H),7.09(dd,J =6.3,2.5 Hz,1H),6.26(t,J =6.1 Hz,1H),3.33(m,2H),3.13(q,J =6.0 Hz,2H),2.89(s,3H)。Using N '-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5- The title compound was prepared according to the procedure of Example 17 Step E. m.j.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj C 12 H 15 BrFN 6 O 4 S (M + H) + The LCMS: m / z = 437.0,439.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 11.49 (s, 1H), 8.90 (s, 1H), 7.17 (m, 2H), 7.09 (dd, J = 6.3, 2.5 Hz, 1H), 6.26 (t, J = 6.1 Hz, 1H), 3.33 (m, 2H), 3.13 (q, J = 6.0 Hz, 2H), 2.89 (s, 3H).

實例3Example 3 4-({3-[(胺基磺醯基)胺基]丙基}胺基)- N -(3-溴-4-氟苯基)- N' -羥基-1,2,5- 二唑-3-甲醯亞胺醯胺 4 - ({3 - [(acyl group sulfo) amino] propyl} amino) - N - (3- bromo-4-fluorophenyl) - N '- hydroxy-1,2,5 Diazole-3-carboxamide

步驟A：3-(4-胺基-1,2,5-二唑-3-基)-4-(3-溴-4-氟苯基)-1,2,4-二唑-5(4H )-酮Step A: 3-(4-Amino-1,2,5- Diazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4- Diazol-5(4 H )-one

使用4-胺基-N -(3-溴-4-氟苯基)-N' -羥基-1,2,5-二唑-3-甲醯亞胺醯胺[參見美國專利申請公開案第2006/0258719號]作為起始物質、根據實例5步驟A 之程序製備所要化合物(98%產率)。C10 H6 BrFN5 O3 (M+H)+ 之LCMS：m/z=342.0,344.0。1 H NMR(400 MHz,DMSO-d 6 )：δ8.06(dd,J =6.2,2.5 Hz,1 H),7.72-7.67(m,1 H),7.58(dd,J =8.7,8.7 Hz,1 H),6.60(s,2 H)。Using 4-amino - N - (3- bromo-4-fluorophenyl) - N '- hydroxy-1,2,5 The oxazol-3-carboxamide amide (see U.S. Patent Application Publication No. 2006/0258719) was prepared as a starting material according to the procedure of Example 5 Step A (yield 98%). C 10 H 6 BrFN 5 O 3 (M + H) + The LCMS: m / z = 342.0,344.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.06 (dd, J = 6.2, 2.5 Hz, 1 H), 7.72-7.67 (m, 1 H), 7.58 (dd, J = 8.7, 8.7 Hz , 1 H), 6.60 (s, 2 H).

步驟B：N -{4-[4-(3-溴-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}-2,2,2-三氟乙醯胺Step B: N -{4-[4-(3-Bromo-4-fluorophenyl)-5-sideoxy-4,5-dihydro-1,2,4- Diazol-3-yl]-1,2,5- Diazol-3-yl}-2,2,2-trifluoroacetamide

使用3-(4-胺基-1,2,5-二唑-3-基)-4-(3-溴-4-氟苯基)-1,2,4-二唑-5(4H )-酮作為起始物質、根據實例5步驟B 之程序製備所要化合物(81%產率)。C12 H5 BrF4 N5 O4 (M+H)+ 之LCMS：m/z=437.9,439.9。1 H NMR(400 MHz,DMSO-d 6 )：δ7.92-7.89(m,1 H),7.54-7.52(m,2 H)。Use 3-(4-amino-1,2,5- Diazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4- Oxadiazol -5 (4 H) - one as a starting material, according to the procedure of Example 5, Step B for preparing the desired compound (81% yield). C 12 H 5 BrF 4 N 5 O 4 (M + H) + The LCMS: m / z = 437.9,439.9. 1 H NMR (400 MHz, DMSO- d 6 ): δ 7.92 - 7.89 (m, 1 H), 7.54 - 7.52 (m, 2 H).

步驟C：4-(3-溴-4-氟苯基)-3-{4-[(3-甲氧基丙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H )-酮Step C: 4-(3-Bromo-4-fluorophenyl)-3-{4-[(3-methoxypropyl)amino]-1,2,5- Diazol-3-yl}-1,2,4- Diazol-5(4 H )-one

在0℃下以偶氮二甲酸二異丙酯(6.7 mL，34 mmol)逐滴處理3-甲氧基丙-1-醇[Fluka產品號38457](3.1 mL，32 mmol)及三苯膦(8.4 g，32 mmol)於四氫呋喃(93 mL)中之溶液。將反應混合物在0℃下攪拌15分鐘，以N -{4-[4-(3-溴-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}-2,2,2-三氟乙醯胺(10 g，23 mmol)於四氫呋喃(47 mL)中之溶液處理且在25℃下攪拌72小時。濃縮反應混合物，以乙酸乙酯(200 mL)稀釋，以三氟乙酸(20 mL)及水(20 mL)處理，且在50℃下加熱6小時。濃縮反應混合物，以乙酸乙酯(200 mL)再稀釋且以水(3×80 mL)、飽和碳酸氫鈉(2×80 mL)及鹽水(80 mL)洗滌，經無水硫酸鈉乾燥、過濾且濃縮成粗殘餘物。在矽膠上純化此物質，以產生呈白色固體狀之所要產物(6.4 g，54%)。C14 H14 BrFN5 O4 (M+H)+ 之LCMS：m/z=414.0,416.0。3-methoxypropan-1-ol [Fluka product number 38457] (3.1 mL, 32 mmol) and triphenylphosphine were treated dropwise at 0 ° C with diisopropyl azodicarboxylate (6.7 mL, 34 mmol). (8.4 g, 32 mmol) in tetrahydrofuran (93 mL). The reaction mixture was stirred at 0 ° C for 15 minutes to give N- {4-[4-(3-bromo-4-fluorophenyl)-5- oxo-4,5-dihydro-1,2,4 - Diazol-3-yl]-1,2,5- A solution of oxazol-3-yl}-2,2,2-trifluoroacetamide (10 g, 23 mmol) in tetrahydrofuran (47 mL). The reaction mixture was concentrated, diluted with EtOAc EtOAc (EtOAc) The reaction mixture was concentrated, washed with EtOAc EtOAc EtOAc (EtOAc) Concentrate to a crude residue. This material was purified on silica gel to give the desired product (6.4 g, 54%). C 14 H 14 BrFN 5 O 4 (M + H) + The LCMS: m / z = 414.0,416.0.

步驟D：4-(3-溴-4-氟苯基)-3-{4-[(3-羥基丙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H )-酮Step D: 4-(3-Bromo-4-fluorophenyl)-3-{4-[(3-hydroxypropyl)amino]-1,2,5- Diazol-3-yl}-1,2,4- Diazol-5(4 H )-one

在-78℃下以二氯甲烷中之1 M三溴化硼(28 mL，28 mmol)處理4-(3-溴-4-氟苯基)-3-{4-[(3-甲氧基丙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H )-酮(6.3 g，14 mmol)於二氯甲烷(60 mL)中之溶液且在25℃下攪拌2小時。將反應混合物冷卻至0℃且以飽和碳酸氫鈉(100 mL)驟冷。分離水層且以二氯甲烷(2×150 mL)萃取。以鹽水(100 mL)洗滌經合併之有機層，經無水硫酸鈉乾燥，過濾且濃縮為灰白色粗固體。在矽膠上純化此物質以產生呈白色固體狀之所要產物(4.0 g，73%)。C13 H12 BrFN5 O4 (M+H)+ 之LCMS：m/z=400.0,402.0。1 H NMR(400 MHz,DMSO-d 6 )：δ8.07(dd,J =6.2,2.5 Hz,1 H),7.72-7.68(m,1 H),7.59(dd,J =8.8,8.6 Hz,1 H),6.54(t,J =5.7 Hz,1 H),4.60(t,J =5.1 Hz,1 H),3.48-3.43(m,2 H),3.32-3.26(m,2 H),1.74-1.67(m,2 H)。Treatment of 4-(3-bromo-4-fluorophenyl)-3-{4-[(3-methoxy) with 1 M boron tribromide (28 mL, 28 mmol) in dichloromethane at -78 °C Propyl)amino]-1,2,5- Diazol-3-yl}-1,2,4- A solution of the oxazol-5( 4H )-one (6.3 g, 14 mmol) in dichloromethane (60 mL)EtOAc. The reaction mixture was cooled to 0.degree. C. and quenched with saturated sodium hydrogen sulfate (100 mL). The aqueous layer was separated and extracted with dichloromethane (2×150 mL). The combined organic layers were washed with EtOAc EtOAc m. This material was purified on silica gel to give the desired product (4.0 g, 73%). C 13 H 12 BrFN 5 O 4 (M + H) + The LCMS: m / z = 400.0,402.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.07 (dd, J = 6.2, 2.5 Hz, 1 H), 7.72-7.68 (m, 1 H), 7.59 (dd, J = 8.8, 8.6 Hz , 1 H), 6.54 (t, J = 5.7 Hz, 1 H), 4.60 (t, J = 5.1 Hz, 1 H), 3.48-3.43 (m, 2 H), 3.32-3.26 (m, 2 H) , 1.74-1.67 (m, 2 H).

步驟E：3-{4-[(3-疊氮基丙基)胺基]-1,2,5-二唑-3-基}-4-(3-溴-4-氟苯基)-1,2,4-二唑-5(4H )-酮Step E: 3-{4-[(3-azidopropyl)amino]-1,2,5- Diazol-3-yl}-4-(3-bromo-4-fluorophenyl)-1,2,4- Diazol-5(4 H )-one

以甲烷磺醯氯(0.75 mL，9,7 mmol)及N ,N -二異丙基乙胺(2.6 mL，15 mmol)處理4-(3-溴-4-氟苯基)-3-{4-[(3-羥基丙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H )-酮(3.0 g，7.5 mmol)於二氯甲烷(27 mL)中之溶液且在25℃下攪拌2小時。以水(20 mL)稀釋反應混合物且以二氯甲烷(20 mL)萃取。分離有機層，經無水硫酸鈉乾燥，過濾且濃縮以產生甲磺酸酯，其不經進一步純化而使用。以疊氮化鈉(0.73 g，11 mmol)處理粗甲磺酸酯於N ,N -二甲基甲醯胺(24 mL)中之溶液且在85℃下加熱2小時。以乙酸乙酯(300 mL)稀釋反應混合物且以水(100 mL)、飽和碳酸氫鈉(100 mL)及鹽水(100 mL)洗滌，經無水硫酸鈉乾燥，過濾且濃縮以產生所要產物(3.2 g，99%)。此物質不經進一步純化而使用。C13 H10 BrFN8 O3 Na(M+Na)+ 之LCMS：m/z=446.9,448.9。Treatment of 4-(3-bromo-4-fluorophenyl)-3-{ with methanesulfonium chloride (0.75 mL, 9,7 mmol) and N , N -diisopropylethylamine (2.6 mL, 15 mmol) 4-[(3-hydroxypropyl)amino]-1,2,5- Diazol-3-yl}-1,2,4- A solution of the oxazol-5( 4H )-one (3.0 g, 7.5 mmol) in dichloromethane (27 mL). The reaction mixture was diluted with water (20 mL) The organic layer was separated, dried over anhydrous sodium A solution of the crude mesylate in N , N -dimethylformamide (24 mL) was taken from sodium azide (0.73 g, &lt The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. g, 99%). This material was used without further purification. C 13 H 10 BrFN 8 O 3 Na (M + Na) + The LCMS: m / z = 446.9,448.9.

步驟F：3-{4-[(3-胺基丙基)胺基]-1,2,5-二唑-3-基}-4-(3-溴-4-氟苯基)-1,2,4-二唑-5(4H )-酮氫碘酸鹽Step F: 3-{4-[(3-Aminopropyl)amino]-1,2,5- Diazol-3-yl}-4-(3-bromo-4-fluorophenyl)-1,2,4- Diazol-5(4 H )-one hydroiodide

以碘化鈉(4.2 g，28 mmol)處理3-{4-[(3-疊氮基丙基)胺基]-1,2,5-二唑-3-基}-4-(3-溴-4-氟苯基)-1,2,4-二唑-5(4H )-酮(2.0 g，4.7 mmol)於甲醇(36 mL)中之溶液且在25℃下攪拌5分鐘。以氯三甲基矽烷(3.6 mL，28 mmol)於甲醇(7 mL)中之溶液逐滴處理反應混合物且在25℃下攪拌40分鐘。將反應混合物緩慢傾注於硫代硫酸鈉(5.0 g，32 mmol)於水(200 mL)中之冷卻於0℃的溶液中。過濾沈澱之固體，以水洗滌且乾燥以產生呈固體狀之所要產物(2.3 g，93%)。C13 H13 BrFN6 O3 (M+H)+ 之LCMS：m/z=399.0,401.0。1 H NMR(400 MHz,DMSO-d 6 )：δ8.08(dd,J =6.1,2.3 Hz,1 H),7.74-7.70(m,1 H),7.60(dd,J =8.8,8.6 Hz,1 H),7.22(br s,2 H),6.69(br s,1 H),2.81-2.77(m,2 H),1.86-1.79(m,2 H)。Treatment of 3-{4-[(3-azidopropyl)amino]-1,2,5- with sodium iodide (4.2 g, 28 mmol) Diazol-3-yl}-4-(3-bromo-4-fluorophenyl)-1,2,4- A solution of the oxazol-5( 4H )-one (2.0 g, 4.7 mmol) in MeOH (3 mL) was stirred for 5 min. The reaction mixture was treated dropwise with a solution of chlorotrimethyl decane (3.6 mL, 28 mmol) in methanol (7 mL) The reaction mixture was slowly poured into a solution of sodium thiosulfate (5.0 g, 32 mmol) in water (200 mL) cooled to 0. The solid which precipitated was filtered, washed with water and dried to give the desired product (2.3 g, 93%). C 13 H 13 BrFN 6 O 3 (M + H) + The LCMS: m / z = 399.0,401.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.08 (dd, J = 6.1, 2.3 Hz, 1 H), 7.74 - 7.70 (m, 1 H), 7.60 (dd, J = 8.8, 8.6 Hz , 1 H), 7.22 (br s, 2 H), 6.69 (br s, 1 H), 2.81-2.77 (m, 2 H), 1.86-1.79 (m, 2 H).

步驟G：N -[3-({4-[4-(3-溴-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}胺基)丙基]磺醯胺Step G: N -[3-({4-[4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4- Diazol-3-yl]-1,2,5- Diazol-3-yl}amino)propyl]sulfonamide

在微波中、在130℃下將3-{4-[(3-胺基丙基)胺基]-1,2,5-二唑-3-基}-4-(3-溴-4-氟苯基)-1,2,4-二唑-5(4H )-酮氫碘酸鹽(150 mg，0.28 mmol)及磺醯胺(160 mg，1.7 mmol)於吡啶(2.5 mL)中之溶液加熱10分鐘。濃縮反應混合物以產生粗殘餘物。藉由製備型LCMS純化此物質，以產生呈固體狀之所要產物(96 mg，71%)。C13 H14 BrFN7 O5 S(M+H)+ 之LCMS：m/z=478.0,480.0。1 H NMR(400 MHz,DMSO-d 6 )：δ8.07(dd,J =6.2,2.5 Hz,1 H),7.73-7.69(m,1 H),7.59(dd,J =8.8,8.6 Hz,1 H),6.57-6.51(m,4 H),3.31-3.26(m,2 H),2.92-2.87(m,2 H),1.79-1.72(m,2 H)。3-{4-[(3-Aminopropyl)amino]-1,2,5- in a microwave at 130 °C Diazol-3-yl}-4-(3-bromo-4-fluorophenyl)-1,2,4- A solution of oxazol-5( 4H )-one hydroiodide (150 mg, 0.28 mmol) and sulfonamide (160 mg, 1.7 mmol) in pyridine (2.5 mL). The reaction mixture was concentrated to give a crude residue. This material was purified by preparative LCMS to give the desired product as a solid (96 mg, 71%). C 13 H 14 BrFN 7 O 5 S (M + H) + The LCMS: m / z = 478.0,480.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.07 (dd, J = 6.2, 2.5 Hz, 1 H), 7.73-7.69 (m, 1 H), 7.59 (dd, J = 8.8, 8.6 Hz , 1 H), 6.57-6.51 (m, 4 H), 3.31-3.26 (m, 2 H), 2.92-2.87 (m, 2 H), 1.79-1.72 (m, 2 H).

步驟H：4-({3-[(胺基磺醯基)胺基]丙基}胺基)-N -(3-溴-4-氟苯基)-N' -羥基-1,2,5-二唑-3-甲醯亞胺醯胺Step H: 4 - ({3 - [( acyl group sulfo) amino] propyl} amino) - N - (3- bromo-4-fluorophenyl) - N '- hydroxy-1,2, 5- Diazole-3-carboxamide

以2 M NaOH(0.3 mL，0.6 mmol)處理N -[3-({4-[4-(3-溴-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}胺基)丙基]磺醯胺(35 mg，73 μmol)於甲醇(1 mL)中之溶液且在25℃下攪拌30分鐘。以乙酸(50 μL，0.9 mmol)處理反應混合物，過濾且藉由製備型LCMS純化以產生呈固體狀之所要產物(14 mg，42%)。C12 H16 BrFN7 O4 S(M+H)+ 之LCMS：m/z=451.8,453.9。1 H NMR(400 MHz,DMSO-d 6 )：δ11.5(s,1 H),8.89(s,1 H),7.17(dd,J =8.8,8.6 Hz,1 H),7.09(dd,J =6.1,2.7 Hz,1 H),6.76-6.72(m,1 H),6.56(dd,J =6.1,6.1 Hz,1 H),6.51(s,2 H),6.17(dd,J =5.9,5.9 Hz,1 H),3.27-3.21(m,2 H),2.94-2.88(m,2 H),1.78-1.71(m,2 H)。Treatment of N- [3-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1) with 2 M NaOH (0.3 mL, 0.6 mmol) , 2,4- Diazol-3-yl]-1,2,5- A solution of oxazol-3-yl}amino)propyl]sulfonamide (35 mg, 73 μmol) in methanol (1 mL) was stirred at 25 ° C for 30 min. The reaction mixture was taken with EtOAc (EtOAc (EtOAc)EtOAc. C 12 H 16 BrFN 7 O 4 S (M + H) + The LCMS: m / z = 451.8,453.9. 1 H NMR (400 MHz, DMSO- d 6 ): δ 11.5 (s, 1 H), 8.89 (s, 1 H), 7.17 (dd, J = 8.8, 8.6 Hz, 1 H), 7.09 (dd, J = 6.1, 2.7 Hz, 1 H), 6.76-6.72 (m, 1 H), 6.56 (dd, J = 6.1, 6.1 Hz, 1 H), 6.51 (s, 2 H), 6.17 (dd, J = 5.9, 5.9 Hz, 1 H), 3.27-3.21 (m, 2 H), 2.94-2.88 (m, 2 H), 1.78-1.71 (m, 2 H).

實例4Example 4 N -(3-溴-4-氟苯基)- N' -羥基-4-({3-[(甲基磺醯基)胺基]丙基}胺基)-1,2,5- 二唑-3-甲醯亞胺醯胺 N - (3- bromo-4-fluorophenyl) - N '- hydroxy-4 - ({3 - [(acyl sulfo methyl) amino] propyl} amino) -1,2,5 Diazole-3-carboxamide

步驟A：{3-[(甲基磺醯基)胺基]丙基}胺基甲酸第三丁酯Step A: {3-[(Methylsulfonyl)amino]propyl}aminocarboxylic acid tert-butyl ester

使用N -(3-胺基丙基)(第三丁氧基)甲醯胺[Aldrich產品號436992]作為起始物質、根據實例17步驟A 之程序製備所要化合物(70%產率)。C4 H13 N2 O2 S([M-Boc+H]+H)+ 之LCMS：m/z=153.1。The desired compound (70% yield) was obtained according to the procedure of Example 17 Step A using N- (3-aminopropyl)(t-butoxy)carbamide (Aldrich product number 436992) as starting material. C 4 H 13 N 2 O 2 S ([M-Boc + H] + H) + The LCMS: m / z = 153.1.

步驟B：N -(3-胺基丙基)甲烷磺醯胺鹽酸鹽Step B: N- (3-Aminopropyl)methanesulfonamide hydrochloride

使用{3-[(甲基磺醯基)胺基]丙基}胺基甲酸第三丁酯作為起始物質、根據實例17步驟B 之程序製備所要化合物。C4 H13 N2 O2 S(M+H)+ 之LCMS：m/z=153.1。Use {3 - [(acyl sulfo methyl) amino] propyl} carbamic acid tert-butyl ester as a starting material, was prepared according to the procedure of Example 17, Step B the desired compound. C 4 H 13 N 2 O 2 S (M + H) + The LCMS: m / z = 153.1.

步驟C：4-胺基-N' -羥基-N -{3-[(甲基磺醯基)胺基]丙基}-1,2,5-二唑-3-甲醯亞胺醯胺Step C: 4- amino - N '- hydroxy - N - {3 - [(acyl sulfo methyl) amino] propyl} -1,2,5 Diazole-3-carboxamide

使用N -(3-胺基丙基)甲烷磺醯胺鹽酸鹽及4-胺基-N -羥基-1,2,5-二唑-3-甲醯亞胺醯氯[根據實例1步驟A至B 製備]作為起始物質、根據實例17步驟C 之程序製備所要化合物(19%產率)。Using N- (3-aminopropyl)methanesulfonamide hydrochloride and 4-amino- N -hydroxy-1,2,5- The oxazol-3-carboximine oxime chloride [prepared according to the procedure of Example 1 Steps A to B ] was used as the starting material to give the desired compound (19% yield) according to the procedure of Example 17 Step C.

步驟D：N' -羥基-4-({3-[(甲基磺醯基)胺基]丙基}胺基)-1,2,5-二唑-3-甲醯亞胺醯胺Step D: N' -hydroxy-4-({3-[(methylsulfonyl)amino)propyl}amino)-1,2,5- Diazole-3-carboxamide

使用4-胺基-N' -羥基-N -{3-[(甲基磺醯基)胺基]丙基}-1,2,5-二唑-3-甲醯亞胺醯胺作為起始物質、根據實例17步驟D 之程序製備所要化合物。C7 H15 N6 O4 S(M+H)+ 之LCMS：m/z=279.0。Using 4-amino- N' -hydroxy- N- {3-[(methylsulfonyl)amino]propyl}-1,2,5- The oxazol-3-carboxamimidamide was used as the starting material to prepare the desired compound according to the procedure of Example 17 Step D. C 7 H 15 N 6 O 4 S (M + H) + The LCMS: m / z = 279.0.

步驟E：N -(3-溴-4-氟苯基)-N' -羥基-4-({3-[(甲基磺醯基)胺基]丙基}胺基)-1,2,5-二唑-3-甲醯亞胺醯胺Step E: N - (3- bromo-4-fluorophenyl) - N '- hydroxy-4 - ({3 - [(acyl sulfo methyl) amino] propyl} amino) -1,2, 5- Diazole-3-carboxamide

使用N' -羥基-4-({3-[(甲基磺醯基)胺基]丙基}胺基)-1,2,5-二唑-3-甲醯亞胺醯胺及3-溴-4-氟苯胺[Oakwood Products,Inc.，產品號013091]作為起始物質、根據實例17步驟E 之程序製備標題化合物(12%產率)。C13 H17 BrFN6 O4 S(M+H)+ 之LCMS：m/z=451.0,453.0。1 H NMR(400 MHz,CD3 OD)：δ7.12(dd,J =5.9,2.4 Hz,1H),7.05(t,J =8.7 Hz,1H),6.83(m,1H),3.39(t,J =6.8 Hz,2H),3.14(t,J =6.6 Hz,2H),2.94(s,3H),1.87(m,2H)。Using N' -hydroxy-4-({3-[(methylsulfonyl)amino)propyl}amino)-1,2,5- The title compound (12% yield) was prepared according to the procedure of Example 17 Step E as the starting material as the starting material of oxazol-3-carboximineamide and 3-bromo-4-fluoroaniline [Oakwood Products, Inc., product number 013091]. rate). C 13 H 17 BrFN 6 O 4 S (M + H) + The LCMS: m / z = 451.0,453.0. 1 H NMR (400 MHz, CD 3 OD): δ 7.12 (dd, J = 5.9, 2.4 Hz, 1H), 7.05 (t, J = 8.7 Hz, 1H), 6.83 (m, 1H), 3.39 (t) , J = 6.8 Hz, 2H), 3.14 (t, J = 6.6 Hz, 2H), 2.94 (s, 3H), 1.87 (m, 2H).

實例5Example 5 4-({2-[(胺基磺醯基)胺基]乙基}胺基)- N -(3-氯-4-氟苯基)- N' -羥基-1,2,5- 二唑-3-甲醯亞胺醯胺 4 - ({2 - [(sulfo amino acyl) amino] ethyl} amino) - N - (3- chloro-4-fluorophenyl) - N '- hydroxy-1,2,5 Diazole-3-carboxamide

步驟A：3-(4-胺基-1,2,5-二唑-3-基)-4-(3-氯-4-氟苯基)-1,2,4-二唑-5(4H )-酮Step A: 3-(4-Amino-1,2,5- Diazol-3-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4- Diazol-5(4 H )-one

以1,1'-羰基二咪唑(53 g，0.32 mol)於四氫呋喃(200 mL)中之溶液處理4-胺基-N -(3-氯-4-氟苯基)-N' -羥基-1,2,5-二唑-3-甲醯亞胺醯胺(80 g，0.29 mol)[參見美國專利申請公開案第2006/0258719號]於四氫呋喃(500 mL)中之溶液且在回流下加熱1小時。使反應混合物冷卻至25℃且濃縮直至大量固體沈澱。以乙酸乙酯(1.5 L)稀釋非均質混合物且以1 N HCl(2×300 mL)、水(300 mL)及鹽水(200 mL)洗滌。分離有機層，經無水硫酸鈉乾燥，過濾且濃縮以產生呈灰白色固體狀之所要產物(88 g，定量)。此物質不經進一步純化而使用。C10 H6 ClFN5 O3 (M+H)+ 之LCMS：m/z=298.0。Treatment of 4-amino- N- (3-chloro-4-fluorophenyl) -N' -hydroxyl with a solution of 1,1'-carbonyldiimidazole (53 g, 0.32 mol) in tetrahydrofuran (200 mL) 1,2,5- A solution of oxazol-3-carboxamimidamide (80 g, 0.29 mol) [see U.S. Patent Application Publication No. 2006/0258719] in tetrahydrofuran (500 mL) and heated under reflux for 1 hour. The reaction mixture was cooled to 25 ° C and concentrated until a large solid precipitated. The heterogeneous mixture was diluted with ethyl acetate (1.5 L) and washed with 1 N HCl (2×300 mL), water (300 mL) and brine (200 mL). The organic layer was separated, dried over anhydrous sodium This material was used without further purification. C 10 H 6 ClFN 5 O 3 (M + H) + The LCMS: m / z = 298.0.

1 H NMR(400 MHz,DMSO-d 6 )：δ7.96(dd,J =6.6,2.3 Hz,1 H),7.69-7.60(m,2 H),6.60(s,2 H)。 1 H NMR (400 MHz, DMSO- d 6): δ7.96 (dd, J = 6.6,2.3 Hz, 1 H), 7.69-7.60 (m, 2 H), 6.60 (s, 2 H).

步驟B：N -{4-[4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}-2,2,2-三氟乙醯胺Step B: N- {4-[4-(3-Chloro-4-fluorophenyl)-5-sideoxy-4,5-dihydro-1,2,4- Diazol-3-yl]-1,2,5- Diazol-3-yl}-2,2,2-trifluoroacetamide

以三氟乙酸酐(14 mL，100 mmol)處理3-(4-胺基-1,2,5-二唑-3-基)-4-(3-氯-4-氟苯基)-1,2,4-二唑-5(4H )-酮(15 g，50 mmol)於二氯甲烷(120 mL)中之溶液，冷卻至0℃，且以吡啶(8.2 mL，100 mmol)處理。將反應混合物在25℃下攪拌10分鐘，冷卻至0℃，且以水(10 mL)驟冷。以乙酸乙酯(500 mL)稀釋反應混合物且以1 N HCl(300 mL)、水(2×200 mL)及鹽水(200 mL)洗滌。分離有機層，經無水硫酸鈉乾燥，過濾且濃縮至約50 mL體積。將此溶液加溫(約40-50℃)且在劇烈攪拌下以己烷(600 mL)處理，隨後以石油醚(200 mL)處理。將混合物在0℃下攪拌30分鐘，且藉由過濾收集固體，以己烷洗滌，且乾燥以產生呈白色固體狀之所要產物(19.7 g，99%)。C12 H5 ClF4 N5 O4 (M+H)+ 之LCMS：m/z=394.0。1 H NMR(400 MHz,DMSO-d 6 )：δ7.82(dd,J =6.6,2.5 Hz,1 H),7.59(dd,J =9.0,9.0 Hz,1 H),7.52-7.47(m,1 H)。Treatment of 3-(4-amino-1,2,5- with trifluoroacetic anhydride (14 mL, 100 mmol) Diazol-3-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4- A solution of the oxazol-5( 4H )-one (15 g, 50 mmol) in dichloromethane (EtOAc)EtOAc. The reaction mixture was stirred at 25 &lt;0&gt;C for 10 min, cooled to 0 &lt;0&gt;C and quenched with water (10 mL). The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to <RTIgt; This solution was warmed (ca. 40-50 ° C) and treated with hexanes (600 mL) with vigorous stirring then with petroleum ether (200 mL). The mixture was stirred at 0&lt;0&gt;C for 30 min, and EtOAc (EtOAc)EtOAc. C 12 H 5 ClF 4 N 5 O 4 (M + H) + The LCMS: m / z = 394.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 7.82 (dd, J = 6.6, 2.5 Hz, 1 H), 7.59 (dd, J = 9.0, 9.0 Hz, 1 H), 7.52-7.47 (m) , 1 H).

步驟C：4-(3-氯-4-氟苯基)-3-(4-{[2-(三苯甲基胺基)乙基]胺基}-1,2,5-二唑-3-基)-1,2,4-二唑-5(4H )-酮Step C: 4-(3-Chloro-4-fluorophenyl)-3-(4-{[2-(tritylamino)ethyl]amino}-1,2,5- Diazol-3-yl)-1,2,4- Diazol-5(4 H )-one

在0℃下以偶氮二甲酸二異丙酯(7.0 mL，35 mmol)逐滴處理2-(三苯甲基胺基)乙醇(10 g，33 mmol)[EP599220及J.Org.Chem .(2001),66 ,7615]及三苯膦(8.7 g，33 mmol)於四氫呋喃(65 mL)中之溶液。將反應混合物在0℃下攪拌15分鐘，以N -{4-[4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}-2,2,2-三氟乙醯胺(9.3 g，24 mmol)於四氫呋喃(28 mL)中之溶液處理且在25℃下攪拌16小時。濃縮反應混合物，以乙酸乙酯(350 mL)稀釋，冷卻至0℃，以1 N HCl(200 mL)處理且在25℃下攪拌1小時。以額外1 N HCl(150 mL)處理反應混合物且在25℃下攪拌3小時。分離有機層，以飽和碳酸氫鈉(200 mL)及鹽水(100 mL)洗滌，經無水硫酸鈉乾燥，過濾且濃縮為黃色發泡體，經由己烷再濃縮以產生油性固體。以甲基第三丁基醚(50 mL)處理油性固體且攪拌以產生非均質混合物。過濾固體，以甲基第三丁基醚(30 mL)洗滌且乾燥以產生呈白色固體狀之所要產物(10 g，74%)。C31 H24 ClFN6 O3 Na(M+Na)+ 之LCMS：m/z=605.2。1 H NMR(300 MHz,DMSO-d 6 )：δ7.97(dd,J =6.7,2.6 Hz,1 H),7.71-7.66(m,1 H),7.60(dd,J =9.1,8.8 Hz,1 H),7.40-7.37(m,6 H),7.28-7.23(m,6 H),7.18-7.12(m,3 H),6.59(dd,J =5.9,5.6 Hz,1 H),3.37-3.31(m,2 H),2.96(dd,J =7.6,7.6 Hz,1 H),2.27-2.19(m,2 H)。2-(Tritylamino)ethanol (10 g, 33 mmol) was treated dropwise at 0 ° C with diisopropyl azodicarboxylate (7.0 mL, 35 mmol) [EP 599220 and J.Org . (2001), 66 , 7615] and a solution of triphenylphosphine (8.7 g, 33 mmol) in tetrahydrofuran (65 mL). The reaction mixture was stirred at 0 ° C for 15 minutes to give N- {4-[4-(3-chloro-4-fluorophenyl)-5- oxo-4,5-dihydro-1,2,4 - Diazol-3-yl]-1,2,5- A solution of oxazol-3-yl}-2,2,2-trifluoroacetamide (9.3 g, 24 mmol) in tetrahydrofuran (28 mL). The reaction mixture was concentrated, diluted with EtOAc EtOAc EtOAc EtOAc. The reaction mixture was treated with additional 1 N HCl (150 mL) and stirred at 25 ° C for 3 h. The organic layer was separated, washed with EtOAc EtOAc m. The oily solid was treated with methyl tert-butyl ether (50 mL) and stirred to give a heterogeneous mixture. The solid was filtered, washed with EtOAc EtOAc (EtOAc) C 31 H 24 ClFN 6 O 3 Na (M + Na) + The LCMS: m / z = 605.2. 1 H NMR (300 MHz, DMSO- d 6 ): δ 7.97 (dd, J = 6.7, 2.6 Hz, 1 H), 7.71-7.66 (m, 1 H), 7.60 (dd, J = 9.1, 8.8 Hz , 1 H), 7.40-7.37 (m, 6 H), 7.28-7.23 (m, 6 H), 7.18-7.12 (m, 3 H), 6.59 (dd, J = 5.9, 5.6 Hz, 1 H), 3.37-3.31 (m, 2 H), 2.96 (dd, J = 7.6, 7.6 Hz, 1 H), 2.27-2.19 (m, 2 H).

步驟D：3-{4-[(2-胺基乙基)胺基]-1,2,5-二唑-3-基}-4-(3-氯-4-氟苯基)-1,2,4-二唑-5(4H )-酮鹽酸鹽Step D: 3-{4-[(2-Aminoethyl)amino]-1,2,5- Diazol-3-yl}-4-(3-chloro-4-fluorophenyl)-1,2,4- Diazol-5(4 H )-one hydrochloride

向4-(3-氯-4-氟苯基)-3-(4-{[2-(三苯甲基胺基)乙基]胺基}-1,2,5-二唑-3-基)-1,2,4-二唑-5(4H )-酮(6.5 g，11 mmol)中添加三異丙基矽烷(3.4 mL，17 mmol)及三氟乙酸(44 mL，570 mmol)之預混合溶液且將所得懸浮液在25℃下攪拌30分鐘。過濾反應混合物且以三氟乙酸洗滌。將濾液濃縮為油狀物，將其以甲醇(25 mL)稀釋，冷卻至0℃，以1,4-二烷中之4 M HCl(14 mL)處理且在25℃下攪拌15分鐘。將混合物濃縮成固體，將其以***(50 mL)處理且過濾。以***(50 mL)洗滌固體且乾燥以產生呈白色固體狀之所要產物(4.1 g，98%)。C12 H11 ClFN6 O3 (M+H)+ 之LCMS：m/z=341.1。1 H NMR(300 MHz,DMSO-d 6 )：δ8.05-8.00(m,4H),7.75-7.69(m,1 H),7.64(dd,J =9.1,8.8 Hz,1 H),6.77(dd,J =5.9,5.9 Hz,1 H),3.54-3.47(m,2 H),3.04-2.99(m,2 H)。To 4-(3-chloro-4-fluorophenyl)-3-(4-{[2-(tritylamino)ethyl]amino}-1,2,5- Diazol-3-yl)-1,2,4- A premixed solution of triisopropylsulfane (3.4 mL, 17 mmol) and trifluoroacetic acid (44 mL, 570 mmol) was added to the oxazol-5( 4H )-one (6.5 g, 11 mmol) and the suspension was obtained. The solution was stirred at 25 ° C for 30 minutes. The reaction mixture was filtered and washed with trifluoroacetic acid. The filtrate was concentrated to an oil which was diluted with methanol (25 mL) and cooled to EtOAc. Treated with 4 M HCl (14 mL) in hexanes and stirred at 25 ° C for 15 min. The mixture was concentrated to a solid which was taken in diethyl ether (50 mL) and filtered. The solid was washed with EtOAc (EtOAc) (EtOAc) C 12 H 11 ClFN 6 O 3 (M + H) + The LCMS: m / z = 341.1. 1 H NMR (300 MHz, DMSO- d 6 ): δ 8.05-8.00 (m, 4H), 7.75-7.69 (m, 1 H), 7.64 (dd, J = 9.1, 8.8 Hz, 1 H), 6.77 (dd, J = 5.9, 5.9 Hz, 1 H), 3.54-3.47 (m, 2 H), 3.04-2.99 (m, 2 H).

步驟E：N -[2-({4-[4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}胺基)乙基]磺醯胺Step E: N- [2-({4-[4-(3-Chloro-4-fluorophenyl)-5-yloxy-4,5-dihydro-1,2,4- Diazol-3-yl]-1,2,5- Diazol-3-yl}amino)ethyl]sulfonamide

在0℃下以第三丁醇(2.2 mL，23 mmol)處理氯磺醯異氰酸酯(2.0 mL，23 mmol)於二氯甲烷(70 mL)中之溶液且在25℃下攪拌1小時。將此混合物添加至3-{4-[(2-胺基乙基)胺基]-1,2,5-二唑-3-基}-4-(3-氯-4-氟苯基)-1,2,4-二唑-5(4H )-酮鹽酸鹽(4.3 g，11 mmol)於二氯甲烷(70 mL)中之懸浮液中。在0℃下以三乙胺(6.3 mL，45 mmol)於二氯甲烷(20 mL)中之溶液處理反應混合物且在25℃下攪拌3小時。將反應混合物以0.1 N HCl稀釋且以乙酸乙酯(2×100 mL)萃取。以鹽水(100 mL)洗滌經合併之有機層，經無水硫酸鈉乾燥，過濾且濃縮為白色固體。以二氯甲烷(100 mL)稀釋白色固體，以三氟乙酸(20 mL)處理且在25℃下攪拌3小時。將反應混合物濃縮為粗殘餘物，將其藉由矽膠層析法純化以產生呈白色固體狀之所要產物(3.7 g，78%)。C12 H12 ClFN7 O5 S(M+H)+ 之LCMS：m/z=420.0。1 H NMR(300 MHz,DMSO-d 6 )：δ7.98(dd,J =6.4,2.1 Hz,1 H),7.70-7.60(m,2 H),6.66(t,J =5.9 Hz,1 H),6.57(s,2 H),6.52(t,J =5.9 Hz,1 H),3.42-3.35(m,2 H),3.13-3.06(m,2 H)。A solution of chlorosulfonium isocyanate (2.0 mL, 23 mmol) in dichloromethane (70 mL) was taken from EtOAc (EtOAc) This mixture was added to 3-{4-[(2-aminoethyl)amino]-1,2,5- Diazol-3-yl}-4-(3-chloro-4-fluorophenyl)-1,2,4- A suspension of oxazol-5( 4H )-one hydrochloride (4.3 g, 11 mmol) in dichloromethane (70 mL). The reaction mixture was treated with a solution of triethylamine (6.3 mL, 45 mmol) in dichloromethane (20 mL). The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) The combined organic layers were washed with EtOAc EtOAc m. The white solid was diluted with dichloromethane (100 mL)EtOAcEtOAcEtOAc The reaction mixture was concentrated to EtOAc (EtOAc m. C 12 H 12 ClFN 7 O 5 S (M + H) + The LCMS: m / z = 420.0. 1 H NMR (300 MHz, DMSO- d 6 ): δ 7.98 (dd, J = 6.4, 2.1 Hz, 1 H), 7.70-7.60 (m, 2 H), 6.66 (t, J = 5.9 Hz, 1 H), 6.57 (s, 2 H), 6.52 (t, J = 5.9 Hz, 1 H), 3.42-3.35 (m, 2 H), 3.13 - 3.06 (m, 2 H).

步驟F：4-({2-[(胺基磺醯基)胺基]乙基}胺基)-N -(3-氯-4-氟苯基)-N' -羥基-1,2,5-二唑-3-甲醯亞胺醯胺Step F: 4 - ({2 - [( sulfo amino acyl) amino] ethyl} amino) - N - (3- chloro-4-fluorophenyl) - N '- hydroxy-1,2, 5- Diazole-3-carboxamide

以2 M NaOH(18 mL，35 mmol)處理N -[2-({4-[4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}胺基)乙基]磺醯胺(3.7 g，8.8 mmol)於甲醇(70 mL)中之溶液且在25℃下攪拌2小時。以6 N HCl使反應混合物驟冷直至約pH 7且在減壓下移除甲醇。過濾沈澱之固體，且以水洗滌以產生呈白色固體狀之所要產物(3.2 g，92%)。C11 H14 ClFN7 O4 S(M+H)+ 之LCMS：m/z=394.0。1 H NMR(400 MHz,DMSO-d 6 )：δ7.96(dd,J =6.8,2.1 Hz,0.05 H),7.32-7.29(m,0.1 H),7.18(dd,J =9.1,9.1 Hz,0.95 H),6.93(dd,J =6.4,2.7 Hz,0.95 H),6.71-6.66(m,0.95 H),6.33(br s,1 H),3.35-3.27(m,2 H),3.10-3.06(m,2 H)。Treatment of N- [2-({4-[4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1) with 2 M NaOH (18 mL, 35 mmol) , 2,4- Diazol-3-yl]-1,2,5- A solution of oxazol-3-yl}amino)ethyl]sulfonamide (3.7 g, 8.8 mmol) in methanol (70 mL) was stirred at 25 ° C for 2 h. The reaction mixture was quenched with 6 N HCl until approximately pH 7 and methanol was removed under reduced pressure. The solid which precipitated was filtered and washed with water to give the desired product (m. C 11 H 14 ClFN 7 O 4 S (M + H) + The LCMS: m / z = 394.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 7.96 (dd, J = 6.8, 2.1 Hz, 0.05 H), 7.32-7.29 (m, 0.1 H), 7.18 (dd, J = 9.1, 9.1 Hz , 0.95 H), 6.93 (dd, J = 6.4, 2.7 Hz, 0.95 H), 6.71-6.66 (m, 0.95 H), 6.33 (br s, 1 H), 3.35-3.27 (m, 2 H), 3.10 -3.06 (m, 2 H).

實例6Example 6 N -(3-氯-4-氟苯基)- N' -羥基-4-({2-[(甲基磺醯基)胺基]乙基}胺基)-1,2,5- 二唑-3-甲醯亞胺醯胺 N - (3- chloro-4-fluorophenyl) - N '- hydroxy-4 - ({2 - [(acyl sulfo methyl) amino] ethyl} amino) -1,2,5 Diazole-3-carboxamide

使用N '-羥基-4-({2-[(甲基磺醯基)胺基]乙基}胺基)-1,2,5-二唑-3-甲醯亞胺醯胺及3-氯-4-氟苯胺[Aldrich，產品號228583]作為起始物質、根據實例17步驟E 之程序製備標題化合物。C12 H15 ClFN6 O4 S(M+H)+ 之LCMS：m/z=393.0。1 H NMR(400 MHz,DMSO-d 6 )：δ11.50(s,1H),8.91(s,1H),7.19(m,2H),6.96(dd,J =6.7,2.5 Hz,1H),6.71(m,1H),6.26(t,J =6.4 Hz,1H),3.32(m,2H),3.13(q,J =5.8 Hz,2H),2.89(s,3H)。Using N '-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5- The title compound was prepared according to the procedure of Example 17, Step E , m. m. m. C 12 H 15 ClFN 6 O 4 S (M + H) + The LCMS: m / z = 393.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 11.50 (s, 1H), 8.91 (s, 1H), 7.19 (m, 2H), 6.96 (dd, J = 6.7, 2.5 Hz, 1H), 6.71 (m, 1H), 6.26 (t, J = 6.4 Hz, 1H), 3.32 (m, 2H), 3.13 (q, J = 5.8 Hz, 2H), 2.89 (s, 3H).

實例7Example 7 4-({3-[(胺基磺醯基)胺基]丙基}胺基)- N -(3-氯-4-氟苯基)- N' -羥基-1,2,5- 二唑-3-甲醯亞胺醯胺 4 - ({3 - [(acyl group sulfo) amino] propyl} amino) - N - (3- chloro-4-fluorophenyl) - N '- hydroxy-1,2,5 Diazole-3-carboxamide

步驟A：3-[(二苯基亞甲基)胺基]丙-1-醇Step A: 3-[(diphenylmethylene)amino]propan-1-ol

以二苯甲酮亞胺(4.4 mL，26 mmol)處理3-胺基-1-丙醇[Aldrich產品號A76400](2.0 mL，26 mmol)於二氯甲烷(79 mL)中之溶液且在25℃下攪拌16小時。過濾反應混合物且濃縮濾液以產生呈油狀之所要產物(6.3 g，定量)。此物質不經進一步純化而使用。C16 H18 NO(M+H)+ 之LCMS：m/z=240.2。A solution of 3-amino-1-propanol [Aldrich product number A76400] (2.0 mL, 26 mmol) in dichloromethane (79 mL) was taken from benzophenoneimide (4.4 mL, 26 mmol) Stir at 25 ° C for 16 hours. The reaction mixture was filtered and the filtrate was evaporated to purified crystals crystals This material was used without further purification. C 16 H 18 NO (M + H) + The LCMS: m / z = 240.2.

步驟B：3-{4-[(3-胺基丙基)胺基]-1,2,5-二唑-3-基}-4-(3-氯-4-氟苯基)-1,2,4-二唑-5(4H )-酮三氟乙酸鹽Step B: 3-{4-[(3-Aminopropyl)amino]-1,2,5- Diazol-3-yl}-4-(3-chloro-4-fluorophenyl)-1,2,4- Diazol-5(4 H )-one trifluoroacetate

在0℃下以偶氮二甲酸二異丙酯(75 μL，0.38 mmol)逐滴處理3-[(二苯基亞甲基)胺基]丙-1-醇(80 mg，0.33 mmol)及三苯膦(93 mg，0.36 mmol)於四氫呋喃(1 mL)中之溶液。將反應混合物在0℃下攪拌15分鐘，以N -{4-[4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}-2,2,2-三氟乙醯胺(100 mg，0.25 mmol)於四氫呋喃(0.5 mL)中之溶液處理且在25℃下攪拌16小時。以三氟乙酸(1 mL)處理反應混合物，在25℃下攪拌3小時，且濃縮為粗殘餘物。藉由製備型LCMS純化此物質，以產生所要產物(18 mg，15%)。C13 H13 ClFN6 O3 (M+H)+ 之LCMS：m/z=355.1。3-[(Diphenylmethylene)amino]propan-1-ol (80 mg, 0.33 mmol) was treated dropwise with diisopropyl azodicarboxylate (75 μL, 0.38 mmol) at 0 °C. A solution of triphenylphosphine (93 mg, 0.36 mmol) in tetrahydrofuran (1 mL). The reaction mixture was stirred at 0 ° C for 15 minutes to give N- {4-[4-(3-chloro-4-fluorophenyl)-5- oxo-4,5-dihydro-1,2,4 - Diazol-3-yl]-1,2,5- A solution of oxazol-3-yl}-2,2,2-trifluoroacetamide (100 mg, 0.25 mmol) in tetrahydrofuran (0.5 mL) was stirred and stirred at 25 ° C for 16 h. The reaction mixture was treated with trifluoroacetic acid (1 mL). This material was purified by preparative LCMS to give the desired product (18 mg, 15%). C 13 H 13 ClFN 6 O 3 (M + H) + The LCMS: m / z = 355.1.

步驟C：4-({3-[(胺基磺醯基)胺基]丙基}胺基)-N -(3-氯-4-氟苯基)-N' -羥基-1,2,5-二唑-3-甲醯亞胺醯胺Step C: 4 - ({3 - [( acyl group sulfo) amino] propyl} amino) - N - (3- chloro-4-fluorophenyl) - N '- hydroxy-1,2, 5- Diazole-3-carboxamide

使用3-{4-[(3-胺基丙基)胺基]-1,2,5-二唑-3-基}-4-(3-氯-4-氟苯基)-1,2,4-二唑-5(4H )-酮三氟乙酸鹽作為起始物質、根據實例15步驟G 之程序製備所要化合物(34%產率)。C12 H16 ClFN7 O4 S(M+H)+ 之LCMS：m/z=408.1。1 H NMR(400 MHz,DMSO-d 6 )：δ8.90(s,1 H),7.20(dd,J =9.2,9.0 Hz,1 H),6.96(dd,J =6.4,2.7 Hz,1 H),6.72-6.69(m,1 H),6.55(t,J =6.0 Hz,1 H),6.51(s,2 H),6.16(t，J =5.9 Hz,1 H),3.28-3.21(m,2 H),2.93-2.87(m,2 H),1.76-1.72(m,2 H)。Using 3-{4-[(3-aminopropyl)amino]-1,2,5- Diazol-3-yl}-4-(3-chloro-4-fluorophenyl)-1,2,4- Oxadiazol -5 (4 H) - one trifluoroacetate as starting materials, according to the procedure of Example 15, Step G Preparation of desired compound (34% yield). C 12 H 16 ClFN 7 O 4 S (M + H) + The LCMS: m / z = 408.1. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.90 (s, 1 H), 7.20 (dd, J = 9.2, 9.0 Hz, 1 H), 6.96 (dd, J = 6.4, 2.7 Hz, 1 H), 6.72-6.69 (m, 1 H), 6.55 (t, J = 6.0 Hz, 1 H), 6.51 (s, 2 H), 6.16 (t, J = 5.9 Hz, 1 H), 3.28-3.21 (m, 2 H), 2.93 - 2.87 (m, 2 H), 1.76-1.72 (m, 2 H).

實例8Example 8 N -(3-氯-4-氟苯基)- N' -羥基-4-({3-[(甲基磺醯基)胺基]丙基}胺基)-1,2,5- 二唑-3-甲醯亞胺醯胺 N - (3- chloro-4-fluorophenyl) - N '- hydroxy-4 - ({3 - [(acyl sulfo methyl) amino] propyl} amino) -1,2,5 Diazole-3-carboxamide

使用N' -羥基-4-({3-[(甲基磺醯基)胺基]丙基}胺基)-1,2,5-二唑-3-甲醯亞胺醯胺[根據實例4步驟A至D 製備]及3-氯-4-氟苯胺[Aldrich，產品號228583]作為起始物質、根據實例4步驟E 之程序製備標題化合物(10%產率)。C13 H17 ClFN6 O4 S(M+H)+ 之LCMS：m/z=407.1。1 H NMR(400 MHz,CD3 OD)：δ7.06(t,J =8.9 Hz,1H),6.98(m,1H),6.80(m,1H),3.73(m,2H),3.28(m,2H),2.94(s,3H),1.28(m,2H)。Using N' -hydroxy-4-({3-[(methylsulfonyl)amino)propyl}amino)-1,2,5- Diazole-3-carboximine decylamine [prepared according to Example 4, Steps A to D ] and 3-chloro-4-fluoroaniline [Aldrich, product No. 228583] were prepared as starting materials according to the procedure of Example 4, Step E. The title compound (10% yield). C 13 H 17 ClFN 6 O 4 S (M + H) + The LCMS: m / z = 407.1. 1 H NMR (400 MHz, CD 3 OD): δ 7.06 (t, J = 8.9 Hz, 1H), 6.98 (m, 1H), 6.80 (m, 1H), 3.73 (m, 2H), 3.28 (m) , 2H), 2.94 (s, 3H), 1.28 (m, 2H).

實例9Example 9 4-({2-[(胺基磺醯基)胺基]乙基}胺基)- N -[4-氟-3-(三氟甲基)苯基]- N' -羥基-1,2,5- 二唑-3-甲醯亞胺醯胺 4 - ({2 - [(sulfo amino acyl) amino] ethyl} amino) - N - [4- fluoro-3- (trifluoromethyl) phenyl] - N '- hydroxy-1, 2,5- Diazole-3-carboxamide

步驟A：N -[4-氟-3-(三氟甲基)苯基]-N' -羥基-4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯胺Step A: N- [4-Fluoro-3-(trifluoromethyl)phenyl] -N' -hydroxy-4-[(2-methoxyethyl)amino]-1,2,5- Diazole-3-carboxamide

使用N -羥基-4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯氯[根據實例1步驟A至E 製備]及3-三氟甲基-4-氟苯胺[Aldrich，產品號217778]作為起始物質、根據實例13步驟A 之程序製備所要化合物(定量產量)。C13 H14 F4 N5 O3 (M+H)+ 之LCMS：m/z=364.0。1 H NMR(400 MHz,CD3 OD)：δ7.15(m,2 H),7.08(m,1H),3.60(t,J =5.3 Hz,2 H),3.46(t,J =5.3 Hz,2 H),3.38(s,3 H)。Using N -hydroxy-4-[(2-methoxyethyl)amino]-1,2,5- Diazole-3-carboximine oxime chloride [prepared according to Example 1 Steps A to E ] and 3-trifluoromethyl-4-fluoroaniline [Aldrich, product number 217778] as starting material, according to Example 13 Step A The procedure is to prepare the desired compound (quantitative yield). C 13 H 14 F 4 N 5 O 3 (M + H) + The LCMS: m / z = 364.0. 1 H NMR (400 MHz, CD 3 OD): δ 7.15 (m, 2 H), 7.08 (m, 1H), 3.60 (t, J = 5.3 Hz, 2 H), 3.46 (t, J = 5.3 Hz , 2 H), 3.38 (s, 3 H).

步驟B：4-[4-氟-3-(三氟甲基)苯基]-3-{4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H )-酮Step B: 4-[4-Fluoro-3-(trifluoromethyl)phenyl]-3-{4-[(2-methoxyethyl)amino]-1,2,5- Diazol-3-yl}-1,2,4- Diazol-5( 4H )-one

使用N -[4-氟-3-(三氟甲基)苯基]-N' -羥基-4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯胺作為起始物質、根據實例13步驟B 之程序製備所要化合物(79%產率)。C14 H12 F4 N5 O4 (M+H)+ 之LCMS：m/z=390.0。1 H NMR(400 MHz,DMSO-d 6 )：δ8.20(dd,J =6.3,2.4 Hz,1 H),8.03(m,1 H),7.76(t,J =9.5 Hz,1 H),6.41(t,J =5.7 Hz,1 H),3.49(t,J =5.5 Hz,2 H),3.39(q,J =5.7 Hz,2 H),3.25(s,3 H)。Using N- [4-fluoro-3-(trifluoromethyl)phenyl] -N' -hydroxy-4-[(2-methoxyethyl)amino]-1,2,5- Oxadiazol-3-amine (PEI) XI as starting material, according to the procedure of Example 13, Step B for preparing the desired compound (79% yield). C 14 H 12 F 4 N 5 O 4 (M + H) + The LCMS: m / z = 390.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.20 (dd, J = 6.3, 2.4 Hz, 1 H), 8.03 (m, 1 H), 7.76 (t, J = 9.5 Hz, 1 H) , 6.41 (t, J = 5.7 Hz, 1 H), 3.49 (t, J = 5.5 Hz, 2 H), 3.39 (q, J = 5.7 Hz, 2 H), 3.25 (s, 3 H).

步驟C：4-[4-氟-3-(三氟甲基)苯基]-3-{4-[(2-羥基乙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H)-酮Step C: 4-[4-Fluoro-3-(trifluoromethyl)phenyl]-3-{4-[(2-hydroxyethyl)amino]-1,2,5- Diazol-3-yl}-1,2,4- Diazol-5(4H)-one

使用4-[4-氟-3-(三氟甲基)苯基]-3-{4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H )-酮作為起始物質、根據實例13步驟C 之程序製備所要化合物(99%產率)。C13 H10 F4 N5 O4 (M+H)+ 之LCMS：m/z=376.0。1 H NMR(400 MHz,DMSO-d 6 )：δ8.22(m,1 H),8.05(m,1 H),7.76(t,J =9.9 Hz,1 H),6.34(t,J =5.7 Hz,1 H),4.87(t,J =5.2 Hz,1 H),3.56(q,J =5.5 Hz,2 H),3.29(q,J =5.7 Hz,2 H)。4-[4-Fluoro-3-(trifluoromethyl)phenyl]-3-{4-[(2-methoxyethyl)amino]-1,2,5- Diazol-3-yl}-1,2,4- Oxadiazol -5 (4H) - one as a starting material, the desired compound (99% yield) was prepared according to the procedure of Example 13, Step C. C 13 H 10 F 4 N 5 O 4 (M + H) + The LCMS: m / z = 376.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.22 (m, 1 H), 8.05 (m, 1 H), 7.76 (t, J = 9.9 Hz, 1 H), 6.34 (t, J = 5.7 Hz, 1 H), 4.87 (t, J = 5.2 Hz, 1 H), 3.56 (q, J = 5.5 Hz, 2 H), 3.29 (q, J = 5.7 Hz, 2 H).

步驟D：甲烷磺酸2-[(4-{4-[4-氟-3-(三氟甲基)苯基]-5-側氧基-4,5-二氫-1,2,4-二唑-3-基}-1,2,5-二唑-3-基)胺基]乙酯Step D: 2-[(4-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-5-sideoxy-4,5-dihydro-1,2,4 methanesulfonate - Diazol-3-yl}-1,2,5- Diazol-3-yl)amino]ethyl ester

使用4-[4-氟-3-(三氟甲基)苯基]-3-{4-[(2-羥基乙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H )-酮作為起始物質、根據實例13步驟D 之程序製備所要化合物(95%產率)。C14 H12 F4 N5 O6 S(M+H)+ 之LCMS：m/z=454.0。1 H NMR(400 MHz,DMSO-d 6 )：δ8.23(dd,J =6.5,2.5 Hz,1 H),8.06(m,1 H),7.76(t,J =9.6 Hz,1 H),6.76(t,J =5.8 Hz,1 H),4.37(t,J =5.4 Hz,2 H),3.60(q,J =5.5 Hz,2 H),3.17(s,3 H)。4-[4-Fluoro-3-(trifluoromethyl)phenyl]-3-{4-[(2-hydroxyethyl)amino]-1,2,5- Diazol-3-yl}-1,2,4- Oxadiazol -5 (4H) - one as a starting material, according to the procedure of Example 13, Step D Preparation of desired compound (95% yield). C 14 H 12 F 4 N 5 O 6 S (M + H) + The LCMS: m / z = 454.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.23 (dd, J = 6.5, 2.5 Hz, 1 H), 8.06 (m, 1 H), 7.76 (t, J = 9.6 Hz, 1 H) , 6.76 (t, J = 5.8 Hz, 1 H), 4.37 (t, J = 5.4 Hz, 2 H), 3.60 (q, J = 5.5 Hz, 2 H), 3.17 (s, 3 H).

步驟E：3-{4-[(2-疊氮基乙基)胺基]-1,2,5-二唑-3-基}-4-[4-氟-3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮Step E: 3-{4-[(2-azidoethyl)amino]-1,2,5- Diazol-3-yl}-4-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4- Diazol-5(4 H )-one

使用甲烷磺酸2-[(4-{4-[4-氟-3-(三氟甲基)苯基]-5-側氧基-4,5-二氫-1,2,4-二唑-3-基}-1,2,5-二唑-3-基)胺基]乙酯作為起始物質、根據實例13步驟E 之程序製備所要化合物(100%之產率)。C13 H9 F4 N6 O3 (M-N2 +H)+ 之LCMS：m/z=372.8。1 H NMR(400 MHz,DMSO-d 6 )：δ8.22(dd,J =6.2,2.4 Hz,1 H),8.05(m,1 H),7.76(t,J =9.6 Hz,1 H),6.75(t,J =5.9 Hz,1 H),3.53(t,J =5.9 Hz,2 H),3.45(q,J =5.6 Hz,2 H)。Using 2-[(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-5-oxo-4,5-dihydro-1,2,4-methanesulfonate Diazol-3-yl}-1,2,5- The oxazol-3-yl)amino]ethyl ester was used as the starting material to give the desired compound (100% yield) according to the procedure of Example 13 Step E. C 13 H 9 F 4 N 6 O 3 (MN 2 + H) + The LCMS: m / z = 372.8. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.22 (dd, J = 6.2, 2.4 Hz, 1 H), 8.05 (m, 1 H), 7.76 (t, J = 9.6 Hz, 1 H) , 6.75 (t, J = 5.9 Hz, 1 H), 3.53 (t, J = 5.9 Hz, 2 H), 3.45 (q, J = 5.6 Hz, 2 H).

步驟F：3-{4-[(2-胺基乙基)胺基]-1,2,5-二唑-3-基}-4-[4-氟-3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮氫碘酸鹽Step F: 3-{4-[(2-Aminoethyl)amino]-1,2,5- Diazol-3-yl}-4-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4- Diazol-5(4 H )-one hydroiodide

使用3-{4-[(2-疊氮基乙基)胺基]-1,2,5-二唑-3-基}-4-[4-氟-3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮作為起始物質、根據實例13步驟F 之程序製備所要化合物(80%產率)。C13 H11 F4 N6 O3 (M+H)+ 之LCMS：m/z=375.0。1 H NMR(400 MHz,DMSO-d 6 )：δ8.20(dd,J =6.2,2.4 Hz,1 H),8.03(m,1 H),7.74(t,J =9.8 Hz,1 H),7.10(br s,0.4 H),6.68(t,J =5.5 Hz,1 H),3.42(q,J =5.8 Hz,2 H),2.95(t,J =6.5 Hz,2 H)。Using 3-{4-[(2-azidoethyl)amino]-1,2,5- Diazol-3-yl}-4-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4- Oxadiazol -5 (4 H) - one as a starting material, according to the procedure of Example 13 Step F for preparing the desired compound (80% yield). C 13 H 11 F 4 N 6 O 3 (M + H) + The LCMS: m / z = 375.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.20 (dd, J = 6.2, 2.4 Hz, 1 H), 8.03 (m, 1 H), 7.74 (t, J = 9.8 Hz, 1 H) , 7.10 (br s, 0.4 H), 6.68 (t, J = 5.5 Hz, 1 H), 3.42 (q, J = 5.8 Hz, 2 H), 2.95 (t, J = 6.5 Hz, 2 H).

步驟G：4-({2-[(胺基磺醯基)胺基]乙基}胺基)-N -[4-氟-3-(三氟甲基)苯基]-N' -羥基-1,2,5-二唑-3-甲醯亞胺醯胺Step G: 4 - ({2 - [( sulfo amino acyl) amino] ethyl} amino) - N - [4- fluoro-3- (trifluoromethyl) phenyl] - N '- hydroxy -1,2,5- Diazole-3-carboxamide

使用3-{4-[(2-胺基乙基)胺基]-1,2,5-二唑-3-基}-4-[4-氟-3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮氫碘酸鹽作為起始物質、根據實例13步驟G 之程序製備標題化合物(55%產率)。C12 H14 F4 N7 O4 S(M+H)+ 之LCMS：m/z=428.0。Using 3-{4-[(2-aminoethyl)amino]-1,2,5- Diazol-3-yl}-4-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4- Oxadiazol -5 (4 H) - -one hydroiodide as the starting material, the title compound was prepared according to the procedure (55% yield) of Example 13 Step G. C 12 H 14 F 4 N 7 O 4 S (M + H) + The LCMS: m / z = 428.0.

1 H NMR(400 MHz,DMSO-d 6 )：δ11.60(s,1 H),9.06(s,1 H),7.30(t,J =10.1 Hz,1 H),7.14(dd,J =6.1,2.7 Hz,1 H),7.03(m,1 H),6.71(t,J =5.3 Hz,1 H),6.58(s,2 H),6.23(t,J =6.2 Hz,1 H),3.36(q,J =6.5 Hz,2 H),3.08(m,2 H)。 1 H NMR (400 MHz, DMSO- d 6 ): δ 11.60 (s, 1 H), 9.06 (s, 1 H), 7.30 (t, J = 10.1 Hz, 1 H), 7.14 (dd, J = 6.1, 2.7 Hz, 1 H), 7.03 (m, 1 H), 6.71 (t, J = 5.3 Hz, 1 H), 6.58 (s, 2 H), 6.23 (t, J = 6.2 Hz, 1 H) , 3.36 (q, J = 6.5 Hz, 2 H), 3.08 (m, 2 H).

實例10Example 10 N -[4-氟-3-(三氟甲基)苯基]- N' -羥基-4-({2-[(甲基磺醯基)胺基]乙基}胺基)-1,2,5- 二唑-3-甲醯亞胺醯胺 N- [4-fluoro-3-(trifluoromethyl)phenyl] -N' -hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1, 2,5- Diazole-3-carboxamide

使用N '-羥基-4-({2-[(甲基磺醯基)胺基]乙基}胺基)-1,2,5-二唑-3-甲醯亞胺醯胺及3-三氟甲基-4-氟苯胺[Aldrich，產品號217778]作為起始物質、根據實例17步驟 E 之程序製備標題化合物。C13 H15 F4 N6 O4 S(M+H)+ 之LCMS：m/z=427.0。1 H NMR(400 MHz,DMSO-d 6 )：δ11.60(s,1H),9.07(s,1H),7.30(t,J =10.1 Hz,1H),7.18(t,J =6.0 Hz,1H),7.13(dd,J =6.0,2.7 Hz,1H),7.03(m,1H),6.27(t,J =6.3 Hz,1H),3.32(m,2H),3.13(q,J =6.0 Hz,2H),2.89(s,3H)。Using N '-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5- The title compound was prepared according to the procedure of Example 17 Step E. m. m. m. C 13 H 15 F 4 N 6 O 4 S (M + H) + The LCMS: m / z = 427.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 11.60 (s, 1H), 9.07 (s, 1H), 7.30 (t, J = 10.1 Hz, 1H), 7.18 (t, J = 6.0 Hz, 1H), 7.13 (dd, J = 6.0, 2.7 Hz, 1H), 7.03 (m, 1H), 6.27 (t, J = 6.3 Hz, 1H), 3.32 (m, 2H), 3.13 (q, J = 6.0) Hz, 2H), 2.89 (s, 3H).

實例11Example 11 4-({3-[(胺基磺醯基)胺基]丙基}胺基)- N -[4-氟-3-(三氟甲基)苯基]- N' -羥基-1,2,5- 二唑-3-甲醯亞胺醯胺 4 - ({3 - [(acyl group sulfo) amino] propyl} amino) - N - [4- fluoro-3- (trifluoromethyl) phenyl] - N '- hydroxy-1, 2,5- Diazole-3-carboxamide

步驟A：4--胺基-N' -羥基-N -(3-甲氧基丙基)-1,2,5-二唑-3-甲醯亞胺醯胺Step A: 4-Amino- N' -hydroxy- N- (3-methoxypropyl)-1,2,5- Diazole-3-carboxamide

使用3-甲氧基-1-丙胺作為起始物質、根據實例1步驟C 之程序製備所要化合物(93%產率)。C7 H14 N5 O3 (M+H)+ 之LCMS：m/z=216.1。The desired compound (93% yield) was obtained according to the procedure of Example 1 Step C using 3-methoxy-1-propylamine as the starting material. C 7 H 14 N 5 O 3 (M + H) + The LCMS: m / z = 216.1.

步驟B：N' -羥基-4-[(3-甲氧基丙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯胺Step B: N' -hydroxy-4-[(3-methoxypropyl)amino]-1,2,5- Diazole-3-carboxamide

使用4-胺基-N' -羥基-N -(3-甲氧基丙基)-1,2,5-二唑-3-甲醯亞胺醯胺作為起始物質、根據實例1步驟D 之程序製備所要化合物(72%產率)。C7 H14 N5 O3 (M+H)+ 之LCMS：m/z=216.1。1 H NMR(300 MHz,DMSO-d 6 )：δ10.4(s,1 H),6.21-6.13(m,3 H),3.37(t,J =6.1 Hz,2 H),3.28-3.21(m,5 H),1.82-1.74(m,2 H)。Using 4-amino- N' -hydroxy- N- (3-methoxypropyl)-1,2,5- The desired compound (72% yield) was prepared according to the procedure of Example 1 Step D. C 7 H 14 N 5 O 3 (M + H) + The LCMS: m / z = 216.1. 1 H NMR (300 MHz, DMSO- d 6 ): δ 10.4 (s, 1 H), 6.21-6.13 (m, 3 H), 3.37 (t, J = 6.1 Hz, 2 H), 3.28-3.21 ( m, 5 H), 1.82-1.74 (m, 2 H).

步驟C：N -羥基-4-[(3-甲氧基丙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯氯Step C: N -Hydroxy-4-[(3-methoxypropyl)amino]-1,2,5- Diazole-3-carboximine

使用N' -羥基-4-[(3-甲氧基丙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯胺作為起始物質、根據實例1步驟E 之程序製備所要化合物(定量產量)。C7 H12 ClN4 O3 (M+H)+ 之LCMS：m/z=235.1。Using N' -hydroxy-4-[(3-methoxypropyl)amino]-1,2,5- The oxazol-3-carboxamimidamide as the starting material was prepared according to the procedure of Example 1, Step E (quantitative yield). C 7 H 12 ClN 4 O 3 (M + H) + The LCMS: m / z = 235.1.

步驟D：N -[4-氟-3-(三氟甲基)苯基]-N' -羥基-4-[(3-甲氧基丙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯胺Step D: N- [4-Fluoro-3-(trifluoromethyl)phenyl] -N' -hydroxy-4-[(3-methoxypropyl)amino]-1,2,5- Diazole-3-carboxamide

使用N -羥基-4-[(3-甲氧基丙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯氯及4-氟-3-(三氟甲基)苯胺作為起始物質、根據實例1步驟F 之程序製備所要化合物(87%產率)。C14 H16 F4 N5 O3 (M+H)+ 之LCMS：m/z=378.1。1 H NMR(400 MHz,DMSO-d 6 )：δ11.5(s,1 H),9.05(s,1 H),7.30(dd,J =10.0,9.6 Hz,1 H),7.13-7.11(m,1 H),7.05-7.00(m,1 H),6.22(t,J =5.7 Hz,1 H),3.35-3.32(m,2 H),3.25-3.19(m,5 H),1.79-1.72(m,2 H)。Using N -hydroxy-4-[(3-methoxypropyl)amino]-1,2,5- The desired compound (87% yield) was prepared according to the procedure of Example 1 Step F. C 14 H 16 F 4 N 5 O 3 (M + H) + The LCMS: m / z = 378.1. 1 H NMR (400 MHz, DMSO- d 6 ): δ 11.5 (s, 1 H), 9.05 (s, 1 H), 7.30 (dd, J =10.0, 9.6 Hz, 1 H), 7.13-7.11 m,1 H), 7.05-7.00 (m, 1 H), 6.22 (t, J = 5.7 Hz, 1 H), 3.35-3.32 (m, 2 H), 3.25-3.19 (m, 5 H), 1.79 -1.72 (m, 2 H).

步驟E：4-[4-氟-3-(三氟甲基)苯基]-3-{4-[(3-甲氧基丙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H )-酮Step E: 4-[4-Fluoro-3-(trifluoromethyl)phenyl]-3-{4-[(3-methoxypropyl)amino]-1,2,5- Diazol-3-yl}-1,2,4- Diazol-5(4 H )-one

使用N -[4-氟-3-(三氟甲基)苯基]-N' -羥基-4-[(3-甲氧基丙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯胺作為起始物質、根據實例1步驟G 之程序製備所要化合物(定量產量)。C15 H14 F4 N5 O4 (M+H)+ 之LCMS：m/z=404.0。Using N- [4-fluoro-3-(trifluoromethyl)phenyl] -N' -hydroxy-4-[(3-methoxypropyl)amino]-1,2,5- The desired compound (quantitative yield) was prepared according to the procedure of Example 1, Step G , using oxazol-3-carboxamimidamine as the starting material. C 15 H 14 F 4 N 5 O 4 (M + H) + The LCMS: m / z = 404.0.

步驟F：4-[4-氟-3-(三氟甲基)苯基]-3-{4-[(3-羥基丙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H )-酮Step F: 4-[4-Fluoro-3-(trifluoromethyl)phenyl]-3-{4-[(3-hydroxypropyl)amino]-1,2,5- Diazol-3-yl}-1,2,4- Diazol-5(4 H )-one

使用4-[4-氟-3-(三氟甲基)苯基]-3-{4-[(3-甲氧基丙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H )-酮作為起始物質、根據實例3步驟D 之程序製備所要化合物(97%產率)。C14 H12 F4 N5 O4 (M+H)+ 之LCMS：m/z=390.0。1 H NMR(300 MHz,DMSO-d 6 )：δ8.20(dd,J =6.4,2.6 Hz,1 H),8.06-8.01(m,1 H),7.75(dd,J =10.0,9.4 Hz,1 H),6.53(t,J =5.7 Hz,1 H),4.59(t,J =5.0 Hz,1 H),3.51-3.42(m,2 H),3.32-3.26(m,2 H),1.73-1.68(m,2 H)。4-[4-Fluoro-3-(trifluoromethyl)phenyl]-3-{4-[(3-methoxypropyl)amino]-1,2,5- Diazol-3-yl}-1,2,4- Oxadiazol -5 (4 H) - one as a starting material, according to the procedure of Example 3, Step D Preparation of desired compound (97% yield). C 14 H 12 F 4 N 5 O 4 (M + H) + The LCMS: m / z = 390.0. 1 H NMR (300 MHz, DMSO- d 6 ): δ 8.20 (dd, J = 6.4, 2.6 Hz, 1 H), 8.06-8.01 (m, 1 H), 7.75 (dd, J =10.0, 9.4 Hz , 1 H), 6.53 (t, J = 5.7 Hz, 1 H), 4.59 (t, J = 5.0 Hz, 1 H), 3.51-3.42 (m, 2 H), 3.32-3.26 (m, 2 H) , 1.73-1.68 (m, 2 H).

步驟G：3-{4-[(3-疊氮基丙基)胺基]-1,2,5-二唑-3-基}-4-[4-氟-3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮Step G: 3-{4-[(3-azidopropyl)amino]-1,2,5- Diazol-3-yl}-4-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4- Diazol-5(4 H )-one

使用4-[4-氟-3-(三氟甲基)苯基]-3-{4-[(3-羥基丙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H )-酮作為起始物質、根據實例3步驟E 之程序製備所要化合物(定量產量)。C14 H10 F4 N8 O3 Na(M+Na)+ 之LCMS：m/z=437.0。4-[4-Fluoro-3-(trifluoromethyl)phenyl]-3-{4-[(3-hydroxypropyl)amino]-1,2,5- Diazol-3-yl}-1,2,4- The desired compound (quantitative yield) was prepared according to the procedure of Example 3, Step E , using oxazol-5( 4H )-one as starting material. C 14 H 10 F 4 N 8 O 3 Na (M + Na) + The LCMS: m / z = 437.0.

步驟H：3-{4-[(3-胺基丙基)胺基]-1,2,5-二唑-3-基}-4-[4-氟-3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮氫碘酸鹽Step H: 3-{4-[(3-Aminopropyl)amino]-1,2,5- Diazol-3-yl}-4-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4- Diazol-5(4 H )-one hydroiodide

使用3-{4-[(3-疊氮基丙基)胺基]-1,2,5-二唑-3-基}-4-[4-氟-3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮作為起始物質、根據實例3步驟F 之程序製備所要化合物(81%產率)。C14 H13 F4 N6 O3 (M+H)+ 之LCMS：m/z=389.1。1 H NMR(300 MHz,DMSO-d 6 )：δ8.18(dd,J =6.4,2.3 Hz,1 H),8.06-8.01(m,1 H),7.72(dd,J =9.7,9.4 Hz,1 H),7.34(br s,2 H),6.71(br s,1 H),2.78-2.73(m,2 H),1.85-1.75(m,2 H)。Using 3-{4-[(3-azidopropyl)amino]-1,2,5- Diazol-3-yl}-4-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4- Oxadiazol -5 (4 H) - one as a starting material, according to the procedure of Example 3, Step F for preparing the desired compound (81% yield). C 14 H 13 F 4 N 6 O 3 (M + H) + The LCMS: m / z = 389.1. 1 H NMR (300 MHz, DMSO- d 6 ): δ 8.18 (dd, J = 6.4, 2.3 Hz, 1 H), 8.06-8.01 (m, 1 H), 7.72 (dd, J = 9.7, 9.4 Hz , 1 H), 7.34 (br s, 2 H), 6.71 (br s, 1 H), 2.78-2.73 (m, 2 H), 1.85-1.75 (m, 2 H).

步驟I：4-({3-[(胺基磺醯基)胺基]丙基}胺基)-N -[4-氟-3-(三氟甲基)苯基]-N' -羥基-1,2,5-二唑-3-甲醯亞胺醯胺Step I: 4 - ({3 - [( acyl group sulfo) amino] propyl} amino) - N - [4- fluoro-3- (trifluoromethyl) phenyl] - N '- hydroxy -1,2,5- Diazole-3-carboxamide

使用3-{4-[(3-胺基丙基)胺基]-1,2,5-二唑-3-基}-4-[4-氟-3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮氫碘酸鹽作為起始物質、根據實例15步驟G 之程序製備所要化合物(60%產率)。C13 H16 F4 N7 O4 S(M+H)+ 之LCMS：m/z=442.0。Using 3-{4-[(3-aminopropyl)amino]-1,2,5- Diazol-3-yl}-4-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4- The oxazol-5( 4H )-one hydroperiodate was used as the starting material to give the desired compound (60% yield) according to the procedure of Example 15 Step G. C 13 H 16 F 4 N 7 O 4 S (M + H) + The LCMS: m / z = 442.0.

1 H NMR(300 MHz,DMSO-d 6 )：δ11.6(s,1 H),9.08(s,1 H),7.31(dd,J =10.0,9.4 Hz,1 H),7.13(dd,J =6.4,2.9 Hz,1 H),7.05-6.99(m,1 H),6.58(t,J =6.0 Hz,1 H),6.52(s,2 H),6.17(t,J =5.9 Hz,1 H),3.28-3.21(m,2 H),2.94-2.87(m,2 H),1.79-1.72(m,2 H)。 1 H NMR (300 MHz, DMSO- d 6 ): δ 11.6 (s, 1 H), 9.08 (s, 1 H), 7.31 (dd, J =10.0, 9.4 Hz, 1 H), 7.13 (dd, J = 6.4, 2.9 Hz, 1 H), 7.05-6.99 (m, 1 H), 6.58 (t, J = 6.0 Hz, 1 H), 6.52 (s, 2 H), 6.17 (t, J = 5.9 Hz) , 1 H), 3.28-3.21 (m, 2 H), 2.94-2.87 (m, 2 H), 1.79-1.72 (m, 2 H).

實例12Example 12 N -[-4-氟-3-(三氟甲基)苯基]- N' -羥基-4-({3-[(甲基磺醯基)胺基]丙基}胺基)-1,2,5- 二唑-3-甲醯亞胺醯胺 N -[-4-fluoro-3-(trifluoromethyl)phenyl] -N' -hydroxy-4-({3-[(methylsulfonyl)amino)propyl}amino)-1 , 2,5- Diazole-3-carboxamide

使用3-{4-[(3-胺基丙基)胺基]-1,2,5-二唑-3-基}-4-[4-氟-3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮氫碘酸鹽作為起始物質、根據實例16 之程序製備所要化合物(70%產率)。C14 H17 F4 N6 O4 S(M+H)+ 之LCMS：m/z=441.1。1 H NMR(400 MHz,DMSO-d 6 )：δ11.6(s,1 H),9.07(s,1 H),7.30(dd,J =10.0,9.6 Hz,1H),7.13(dd,J =6.2,2.5 Hz,1 H),7.05-7.02(m,2 H),6.19(t,J =5.8 Hz,1 H),3.27-3.21(m,2 H),2.99-2.94(m,2 H),2.87(s,3 H),1.76-1.72(m,2 H)。Using 3-{4-[(3-aminopropyl)amino]-1,2,5- Diazol-3-yl}-4-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4- The oxazol-5( 4H )-one hydroiodide was used as the starting material to give the desired compound (70% yield) according to the procedure of Example 16 . C 14 H 17 F 4 N 6 O 4 S (M + H) + The LCMS: m / z = 441.1. 1 H NMR (400 MHz, DMSO- d 6 ): δ 11.6 (s, 1 H), 9.07 (s, 1 H), 7.30 (dd, J =10.0, 9.6 Hz, 1H), 7.13 (dd, J =6.2, 2.5 Hz, 1 H), 7.05-7.02 (m, 2 H), 6.19 (t, J = 5.8 Hz, 1 H), 3.27-3.21 (m, 2 H), 2.99-2.94 (m, 2) H), 2.87 (s, 3 H), 1.76-1.72 (m, 2 H).

實例13Example 13 4-({2-[(胺基磺醯基)胺基]乙基}胺基)- N' -羥基- N -[3-(三氟甲基)苯基]-1,2,5- 二唑-3-甲醯亞胺醯胺 4 - ({2 - [(sulfo amino acyl) amino] ethyl} amino) - N '- hydroxy - N - [3- (trifluoromethyl) phenyl] -1,2,5 Diazole-3-carboxamide

步驟A：N' -羥基-4-[(2-甲氧基乙基)胺基]-N -[3-(三氟甲基)苯基]-1,2,5-二唑-3-甲醯亞胺醯胺Step A: N '- hydroxy-4 - [(2-methoxyethyl) amino] - N - [3- (trifluoromethyl) phenyl] -1,2,5 Diazole-3-carboxamide

在水(10 mL)中攪拌N -羥基-4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯氯(1.3 g，5.0 mmol)[根據實例1步驟A 至E 製備]且溫至60℃歷時5分鐘。以一份添加3-(三氟甲基)苯胺[Aldrich，產品號A41801](880 mg，5.5 mmol)且將反應物攪拌15分鐘。在60℃下保持的同時，經5分鐘逐滴添加碳酸氫鈉(630 mg，7.5 mmol)於水(10 mL)中之溶液。將反應物在60℃下再攪拌50分鐘，且接著使其冷卻至室溫。向燒瓶中添加乙酸乙酯(20 mL)及鹽水(30 mL)且收集有機層。以乙酸乙酯(2×20 mL)萃取水層且經硫酸鈉乾燥經合併之有機物。真空移除溶劑以產生呈橙色固體狀之所要產物(1.4 g，80%)。C13 H15 F3 N5 O3 (M+H)+ 之LCMS計算值：m/z=346.1。1 H NMR(400 MHz,CD3 OD)：δ7.36(t,J =8.2 Hz,1H),7.23(d,J =7.6 Hz,1H),7.09(s,1H),7.02(d,J =8.2 Hz,1H),3.60(t,J =5.2 Hz,2H),3.46(t,J =5.2 Hz,2H),3.38(s,3H)。Stir N -hydroxy-4-[(2-methoxyethyl)amino]-1,2,5- in water (10 mL) Diazole-3-carboximine oxime chloride (1.3 g, 5.0 mmol) [prepared according to Example 1 Steps A to E ] and warmed to 60 °C for 5 minutes. 3-(Trifluoromethyl)aniline [Aldrich, product number A41801] (880 mg, 5.5 mmol) was added in one portion and the mixture was stirred 15 min. While maintaining at 60 ° C, a solution of sodium bicarbonate (630 mg, 7.5 mmol) in water (10 mL) was added dropwise over 5 min. The reaction was stirred at 60 ° C for an additional 50 minutes and then allowed to cool to room temperature. Ethyl acetate (20 mL) and brine (30 mL) were added and the organic layer was collected. The aqueous layer was extracted with EtOAc (2×20 mL). The solvent was removed in vacuo to give the desired product (1. 4 g, 80%). C 13 H (M + H) + LCMS calcd of 15 F 3 N 5 O 3: m / z = 346.1. 1 H NMR (400 MHz, CD 3 OD): δ 7.36 (t, J = 8.2 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.09 (s, 1H), 7.02 (d, J) = 8.2 Hz, 1H), 3.60 (t, J = 5.2 Hz, 2H), 3.46 (t, J = 5.2 Hz, 2H), 3.38 (s, 3H).

步驟B：3-{4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-基}-4-[3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮Step B: 3-{4-[(2-methoxyethyl)amino]-1,2,5- Diazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4- Diazol-5(4 H )-one

將N' -羥基-4-[(2-甲氧基乙基)胺基]-N -[3-(三氟甲基)苯基]-1,2,5-二唑-3-甲醯亞胺醯胺(1.4 g，3.80 mmol)及1,1'-羰基二咪唑(1.16 g，7.16 mmol)溶解於乙酸乙酯(20 mL)中。將反應混合物在70℃下加熱40分鐘。再添加1,1'-羰基二咪唑(0.26 g，1.16 mmol)。在70℃下再攪拌50分鐘後，使反應物冷卻至室溫。添加乙酸乙酯(20 mL)且以水中之1 N HCl(2×20 mL)洗滌粗反應物。添加鹽水以有助於第一洗滌液之分離。經硫酸鈉乾燥有機層且真空中濃縮。藉由矽膠急驟層析法(使用己烷中之乙酸乙酯作為溶離劑)純化以產生所要產物(1.3 g，90%)。C14 H13 F3 N5 O4 (M+H)+ 之LCMS計算值：m/z=372.0。1 H NMR(400 MHz,DMSO-d 6 )：δ8.07(s,1H),7.92(m,2H),7.79(t,J =8.1 Hz,1H),6.42(t,J =6.0 Hz,1H),3.47(t,J =5.8 Hz,2H),3.38(q,J =5.0 Hz,2H),3.24(s,3H)。 Of N '- hydroxy-4 - [(2-methoxyethyl) amino] - N - [3- (trifluoromethyl) phenyl] -1,2,5 The oxazol-3-carboxamimidamide (1.4 g, 3.80 mmol) and 1,1'-carbonyldiimidazole (1.16 g, 7.16 mmol) were dissolved in ethyl acetate (20 mL). The reaction mixture was heated at 70 ° C for 40 minutes. Further 1,1'-carbonyldiimidazole (0.26 g, 1.16 mmol) was added. After stirring at 70 ° C for an additional 50 minutes, the reaction was allowed to cool to room temperature. Ethyl acetate (20 mL) was added and the crude material was washed with 1 N EtOAc (2×20 mL). Brine is added to aid in the separation of the first wash liquor. The organic layer was dried over sodium sulfate and concentrated in vacuo. Purification by silica gel flash chromatography (using ethyl acetate in hexanes as solvent) afforded the desired product (1.3 g, 90%). C 14 H (M + H) + LCMS calcd of 13 F 3 N 5 O 4: m / z = 372.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.07 (s, 1H), 7.92 (m, 2H), 7.79 (t, J = 8.1 Hz, 1H), 6.42 (t, J = 6.0 Hz, 1H), 3.47 (t, J = 5.8 Hz, 2H), 3.38 (q, J = 5.0 Hz, 2H), 3.24 (s, 3H).

步驟C：3-{4-[(2-羥基乙基)胺基]-1,2,5-二唑-3-基}-4-[3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮Step C: 3-{4-[(2-hydroxyethyl)amino]-1,2,5- Diazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4- Diazol-5(4 H )-one

在氮氣氛圍下，在圓底燒瓶中，在二氯甲烷(11 mL)中攪拌3-{4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-基}-4-[3-(三氟甲基)苯基]-1,2,4-二唑-5(4H)-酮(1.3 g，3.6 mmol)。使溫度達到-78℃且經15分鐘逐滴添加1.0 M三溴化硼於二氯甲烷(7.9 mL，7.9 mmol)中之溶液。經45分鐘使反應物溫至室溫且在室溫下繼續攪拌額外45分鐘。使反應物冷卻至0℃且經15分鐘逐滴添加碳酸氫鈉於水中之飽和溶液(25 mL)。溫至室溫後，向燒瓶中添加乙酸乙酯(10 mL)及水(10 mL)。收集有機層且以乙酸乙酯(2×20 mL)萃取水層。經硫酸鈉乾燥經合併之有機層後，真空移除溶劑以產生所要產物(1.0 g，81%)。C13 H11 F3 N5 O4 (M+H)+ 之LCMS計算值：m/z=358.0。1 H NMR(400 MHz,DMSO-d 6 )：δ8.08(s,1H),7.93(t,J =8.2 Hz,2H),7.79(t,J =8.2 Hz,1H),6.35(t,J =5.7 Hz,1H),4.86(br s,1H),3.55(t,J =6.0 Hz,2H),3.28(m,2H)。Stirring 3-{4-[(2-methoxyethyl)amino]-1,2,5- in dichloromethane (11 mL) in a round bottom flask under a nitrogen atmosphere. Diazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4- Diazol-5(4H)-one (1.3 g, 3.6 mmol). The temperature was brought to -78 ° C and a solution of 1.0 M boron tribromide in dichloromethane (7.9 mL, 7.9 mmol) was added dropwise over 15 min. The reaction was allowed to warm to room temperature over 45 min and stirring was continued at room temperature for an additional 45 min. The reaction was cooled to 0.degree. C. and a saturated solution (25 mL) of sodium bicarbonate in water was added dropwise over 15 min. After warming to room temperature, ethyl acetate (10 mL) and water (10 mL) were added to the flask. The organic layer was collected and extracted with ethyl acetate (2×20 mL). After drying the combined organic layers over sodium sulfate, solvent was evaporated in vacuo to give the desired product (l. C 13 H (M + H) + LCMS calcd of 11 F 3 N 5 O 4: m / z = 358.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.08 (s, 1H), 7.93 (t, J = 8.2 Hz, 2H), 7.79 (t, J = 8.2 Hz, 1H), 6.35 (t, J = 5.7 Hz, 1H), 4.86 (br s, 1H), 3.55 (t, J = 6.0 Hz, 2H), 3.28 (m, 2H).

步驟D：甲烷磺酸2-[(4-{5-側氧基-4-[3-(三氟甲基)苯基]-4,5-二氫-1,2,4-二唑-3-基}-1,2,5-二唑-3-基)胺基]乙酯Step D: 2-[(4-{5-Phenoxy-4-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1,2,4-methanesulfonic acid Diazol-3-yl}-1,2,5- Diazol-3-yl)amino]ethyl ester

向3-{4-[(2-羥基乙基)胺基]-1,2,5-二唑-3-基}-4-[3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮(1.0 g，2.9 mmol)於乙酸乙酯(8.5 mL)中之溶液中以一份添加甲烷磺醯氯(0.29 mL，3.7 mmol)。將反應物攪拌5分鐘且亦以一份添加三乙胺(0.52 mL，3.7 mmol)。再攪拌10分鐘後，在添加水(5 mL)下中止反應。以乙酸乙酯(2×5 mL)萃取產物，經硫酸鈉乾燥且真空濃縮以產生所要產物(1.2 g，99%)。C14 H13 F3 N5 O6 S(M+H)+ 之LCMS計算值：m/z=436.0。1 H NMR(400 MHz,DMSO-d 6 )：δ8.10(s,1H),7,92(m,2H),7.80(t,J =8.2 Hz,1H),6.77(t,J =5.9 Hz,1H),4.36(t,J =5.5 Hz,2H),3.58(m,2H),3.17(s,3H)。To 3-{4-[(2-hydroxyethyl)amino]-1,2,5- Diazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4- To a solution of the oxazol-5( 4H )-one (1.0 g, 2.9 mmol) in EtOAc (EtOAc) The reaction was stirred for 5 min and triethylamine (0.52 mL, EtOAc. After stirring for an additional 10 minutes, the reaction was quenched with water (5 mL). The product was extracted with EtOAc (EtOAc (EtOAc) C 14 H (M + H) + LCMS calcd of 13 F 3 N 5 O 6 S : m / z = 436.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.10 (s, 1H), 7.92 (m, 2H), 7.80 (t, J = 8.2 Hz, 1H), 6.77 (t, J = 5.9 Hz, 1H), 4.36 (t, J = 5.5 Hz, 2H), 3.58 (m, 2H), 3.17 (s, 3H).

步驟E：3-{4-[(2-疊氮基乙基)胺基]-1,2,5-二唑-3-基}-4-[3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮Step E: 3-{4-[(2-azidoethyl)amino]-1,2,5- Diazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4- Diazol-5(4 H )-one

將甲烷磺酸2-[(4-{5-側氧基-4-[3-(三氟甲基)苯基]-4,5-二氫-1,2,4-二唑-3-基}-1,2,5-二唑-3-基)胺基]乙酯(1.2 g，2.9 mmol)溶解於N,N -二甲基甲醯胺(2.7 mL)中。以一份添加疊氮化鈉(280 mg，4.3 mmol)之後，使溫度達到65℃且將反應物攪拌6小時。冷卻回至室溫後，添加水(10 mL)以中止反應。以乙酸乙酯(3×10 mL)萃取產物且經硫酸鈉乾燥經合併之有機層。真空移除溶劑以產生所要產物(1.05 g，96%)。C13 H10 F3 N6 O3 (M-N2 +H)+ 之LCMS計算值：m/z=355.0。1 H NMR(400 MHz,DMSO-d 6 )：δ8.09(s,1H),7.93(m,2H),7.79(t,J =8.2 Hz,1H),6.75(t,J =5.8 Hz,1H),3.52(t,J =5.7 Hz,2H),3.44(q,J =5.5 Hz,2H)。2-[(4-{5-Phenoxy-4-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1,2,4-methanesulfonic acid Diazol-3-yl}-1,2,5- The oxazol-3-yl)amino]ethyl ester (1.2 g, 2.9 mmol) was dissolved in N,N -dimethylformamide (2.7 mL). After a portion of sodium azide (280 mg, 4.3 mmol) was added, the temperature was brought to 65 ° C and the mixture was stirred for 6 hours. After cooling to room temperature, water (10 mL) was added to quench the reaction. The product was extracted with EtOAc (3×10 mL). The solvent was removed in vacuo to give the desired product (1.05 g, 96%). C 13 H (MN 2 + H ) + LCMS calcd of 10 F 3 N 6 O 3: m / z = 355.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.09 (s, 1H), 7.93 (m, 2H), 7.79 (t, J = 8.2 Hz, 1H), 6.75 (t, J = 5.8 Hz, 1H), 3.52 (t, J = 5.7 Hz, 2H), 3.44 (q, J = 5.5 Hz, 2H).

步驟F：3-{4-[(2-胺基乙基)胺基]-1,2,5-二唑-3-基}-4-[3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮氫碘酸鹽Step F: 3-{4-[(2-Aminoethyl)amino]-1,2,5- Diazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4- Diazol-5(4 H )-one hydroiodide

向3-{4-[(2-疊氮基乙基)胺基]-1,2,5-二唑-3-基}-4-[3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮(1.05 g，2.8 mmol)於甲醇(12 mL)中之溶液中添加碘化鈉(2.5 g，17 mmol)。攪拌10分鐘後，經15分鐘逐滴添加氯三甲基矽烷(2.1 mL，17 mmol)於甲醇(1.41 mL)中之溶液。將反應物繼續攪拌40分鐘,且接著以一份添加硫代硫酸鈉(2.7 g，17 mmol)於水(12.5 mL)中之溶液。經添加硫代硫酸鈉溶液後，米色固體沈澱且藉由真空過濾收集。以水(2×10 mL)沖洗固體且在真空下乾燥隔夜以產生所要產物。固體亦自濾液沈澱且將其藉由真空過濾收集。在漏斗中以水(3×10 mL)洗滌後，將產物在真空下乾燥隔夜。將固體以乙酸乙酯(3.8 mL)洗滌1小時成漿液且藉由過濾收集。以乙酸乙酯(2×2 mL)沖洗後且乾燥隔夜後，獲得額外產物。總共獲得760 mg呈氫碘酸鹽形式之所要產物(57%)。C13 H12 F3 N6 O3 (M+H)+ 之LCMS計算值：m/z=357.1。1 H NMR(400 MHz,DMSO-d 6 )：δ8.10(s,1H),7.95(m,2H),7.81(t,J =8.1 Hz,1H),7.68(br s,2H),6.74(t,J =6.7 Hz,1H),3.49(m,2H),3.03(t,J =6.7 Hz,2H)。To 3-{4-[(2-azidoethyl)amino]-1,2,5- Diazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4- Sodium iodide (2.5 g, 17 mmol) was added to a solution of the oxazol-5( 4H )-one (1.05 g, 2.8 mmol) in methanol (12 mL). After stirring for 10 minutes, a solution of chlorotrimethyldecane (2.1 mL, 17 mmol) in methanol (1.41 mL). The reaction was stirred for a further 40 minutes and then a solution of sodium thiosulfate (2.7 g, 17 mmol) in water (12.5 mL) was added. After addition of the sodium thiosulfate solution, a beige solid precipitated and was collected by vacuum filtration. The solid was rinsed with water (2 x 10 mL) and dried under vacuum overnight to yield the desired product. The solid also precipitated from the filtrate and was collected by vacuum filtration. After washing with water (3 x 10 mL) in a funnel, the product was dried under vacuum overnight. The solid was washed with ethyl acetate (3.8 mL) for 1 hour to be slurried and collected by filtration. After washing with ethyl acetate (2 x 2 mL) and drying overnight, additional product was obtained. A total of 760 mg of the desired product (57%) was obtained in the form of hydroiodide. C 13 (M + H) + LCMS calc the H 12 F 3 N 6 O 3 : m / z = 357.1. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.10 (s, 1H), 7.95 (m, 2H), 7.81 (t, J = 8.1 Hz, 1H), 7.68 (br s, 2H), 6.74 (t, J = 6.7 Hz, 1H), 3.49 (m, 2H), 3.03 (t, J = 6.7 Hz, 2H).

步驟G：4-({2-[(胺基磺醯基)胺基]乙基}胺基)-N '-羥基-N -[3-(三氟甲基)苯基]-1,2,5-二唑-3-甲醯亞胺醯胺Step G: 4 - ({2 - [( sulfo amino acyl) amino] ethyl} amino) - N '- hydroxy - N - [3- (trifluoromethyl) phenyl] -1,2 , 5- Diazole-3-carboxamide

在0℃下、在氮氣氛圍下向氯磺醯異氰酸酯(9.2 μL，0.11 mmol)於二氯甲烷(0.24 mL)中之溶液中以逐滴方式添加第三丁醇(10 μL，0.11 mmol)。將溶液在室溫下攪拌1小時以獲得[氯磺醯基]胺基甲酸第三丁酯之溶液。To a solution of chlorosulfonium isocyanate (9.2 μL, 0.11 mmol) in dichloromethane (0.24 mL) was added dropwise EtOAc (10 μL, 0.11 mmol). The solution was stirred at room temperature for 1 hour to obtain a solution of [chlorosulfonyl]aminobutyl formate.

在單獨燒瓶中，將3-{4-[(2-胺基乙基)胺基]-1,2,5-二唑-3-基}-4-[3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮氫碘酸鹽(26 mg，0.053 mmol)懸浮於二氯甲烷(0.5 mL)中。建立氮氣氛圍且使溫度達到0℃。經5分鐘向胺鹽之經攪拌懸浮液中添加[氯磺醯基]胺基甲酸第三丁酯溶液(如上文所述製備)。10分鐘後，逐滴添加三乙胺(37 μL，0.27 mmol)。將反應混合物在室溫下攪拌1.5小時。真空濃縮後，以三氟乙酸(0.5 mL，6 mmol)處理殘餘物。將其攪拌1小時，且將混合物在真空中再次濃縮至乾。將經乾燥固體懸浮於甲醇(0.5 mL)中且以一份添加水中之2.0 N NaOH(0.53 mL，1.1 mmol)。將反應物加熱至45℃且攪拌30分鐘。以乙酸(60 μL，1.1 mmol)中和後，藉由製備型LCMS純化產物以產生所要產物(8.5 mg，39%)。C12 H15 F3 N7 O4 S(M+H)+ 之LCMS計算值：m/z=410.0。1 H NMR(400 MHz,CD3 OD)：δ7.36(t,J =7.8 Hz,1H),7.23(d,J =7.8 Hz,1H),7.10(s,1H),7.03(d,J =7.8 Hz,1H),3.48(m,2H),3.29(m,2H)。In a separate flask, 3-{4-[(2-aminoethyl)amino]-1,2,5- Diazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4- The oxazol-5( 4H )-one hydroiodide (26 mg, 0.053 mmol) was suspended in dichloromethane (0.5 mL). A nitrogen atmosphere was established and the temperature was brought to 0 °C. A solution of [chlorosulfonyl] carbamic acid tert-butyl ester (prepared as described above) was added to the stirred suspension of the amine salt over 5 minutes. After 10 minutes, triethylamine (37 μL, 0.27 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1.5 hours. After concentration in vacuo, the residue was crystallised eluted elute It was stirred for 1 hour and the mixture was again concentrated to dryness in vacuo. The dried solid was suspended in methanol (0.5 mL) and EtOAc (0.53 mL, &lt The reaction was heated to 45 ° C and stirred for 30 minutes. After neutralization with acetic acid (60 [mu]L, 1.1 mmol), product was purified by preparative LCMS to give the desired product (8.5 mg, 39%). C 12 H 15 F 3 N 7 O 4 S (M + H) + The LCMS calc: m / z = 410.0. 1 H NMR (400 MHz, CD 3 OD): δ 7.36 (t, J = 7.8 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.10 (s, 1H), 7.03 (d, J) = 7.8 Hz, 1H), 3.48 (m, 2H), 3.29 (m, 2H).

實例14Example 14 N' -羥基-4-({2-[(甲基磺醯基)胺基]乙基}胺基)- N -[3-(三氟甲基)苯基]-1,2,5- 二唑-3-甲醯亞胺醯胺 N '- hydroxy-4 - ({2 - [(acyl sulfo methyl) amino] ethyl} amino) - N - [3- (trifluoromethyl) phenyl] -1,2,5 Diazole-3-carboxamide

使用N '-羥基-4-({2-[(甲基磺醯基)胺基]乙基}胺基)-1,2,5-二唑-3-甲醯亞胺醯胺及3-三氟甲基苯胺[Aldrich，產品號A41801]作為起始物質、根據實例17步驟E 之程序製備標題化合物。C13 H16 F3 N6 O4 S(M+H)+ 之LCMS：m/z=409.1。1 H NMR(500 MHz,DMSO-d 6 )：δ11.63(s,1H),9.08(s,1H),7.39(t,J =7.6 Hz,1H),7.21(m,2H),7.10(s,1H),6.99(d,J =8.1 Hz,1H),6.28(t,J =5.4 Hz,1H),3.36(q,J =5.8 Hz,2H),3.17(q,J =5.8 Hz,2H),2.91(s,3H)。Using N '-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5- The title compound was prepared according to the procedure of Example 17 Step E. m. m. m. C 13 H 16 F 3 N 6 O 4 S (M + H) + The LCMS: m / z = 409.1. 1 H NMR (500 MHz, DMSO- d 6 ): δ 11.63 (s, 1H), 9.08 (s, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.21 (m, 2H), 7.10 ( s, 1H), 6.99 (d, J = 8.1 Hz, 1H), 6.28 (t, J = 5.4 Hz, 1H), 3.36 (q, J = 5.8 Hz, 2H), 3.17 (q, J = 5.8 Hz, 2H), 2.91 (s, 3H).

實例15Example 15 4-({3-[(胺基磺醯基)胺基]丙基}胺基)- N' -羥基- N -[3-(三氟甲基)苯基]-1,2,5- 二唑-3-甲醯亞胺醯胺 4 - ({3 - [(acyl group sulfo) amino] propyl} amino) - N '- hydroxy - N - [3- (trifluoromethyl) phenyl] -1,2,5 Diazole-3-carboxamide

步驟A：3-(4-胺基-1,2,5-二唑-3-基)-4-[3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮Step A: 3-(4-Amino-1,2,5- Diazol-3-yl)-4-[3-(trifluoromethyl)phenyl]-1,2,4- Diazol-5(4 H )-one

使用4-胺基-N' -羥基-N -[3-(三氟甲基)苯基]-1,2,5-二唑-3-甲醯亞胺醯胺[參見美國專利申請公開案第2006/0258719號]作為起始物質、根據實例5步驟A 之程序製備所要化合物(97%產率)。C11 H7 F3 N5 O3 (M+H)+ 之LCMS：m/z=314.1。Using 4-amino- N' -hydroxy- N- [3-(trifluoromethyl)phenyl]-1,2,5- The oxazol-3-carboxamide amide (see U.S. Patent Application Publication No. 2006/0258719) was used as the starting material to prepare the desired compound (97% yield) according to the procedure of Example 5 Step A. C 11 H 7 F 3 N 5 O 3 (M + H) + The LCMS: m / z = 314.1.

步驟B：2,2,2-三氟-N -(4-{5-側氧基-4-[3-(三氟甲基)苯基]-4,5-二氫-1,2,4-二唑-3-基}-1,2,5-二唑-3-基)乙醯胺Step B: 2,2,2-Trifluoro- N- (4-{5-o-oxy-4-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1,2, 4- Diazol-3-yl}-1,2,5- Diazol-3-yl)acetamide

使用3-(4-胺基-1,2,5-二唑-3-基)-4-[3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮作為起始物質、根據實例5步驟B 之程序製備所要化合物(90%產率)。C13 H6 F6 N5 O4 (M+H)+ 之LCMS：m/z=410.0。1 H NMR(400 MHz,DMSO-d 6 )：δ7.91-7.88(m,2 H),7.76-7.69(m,2 H)。Use 3-(4-amino-1,2,5- Diazol-3-yl)-4-[3-(trifluoromethyl)phenyl]-1,2,4- Oxadiazol -5 (4 H) - one as a starting material, according to the procedure of Example 5, Step B for preparing the desired compound (90% yield). C 13 H 6 F 6 N 5 O 4 (M + H) + The LCMS: m / z = 410.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 7.91 - 7.88 (m, 2 H), 7.76 - 7.69 (m, 2 H).

步驟C：3-{4-[(3-甲氧基丙基)胺基]-1,2,5-二唑-3-基}-4-[3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮Step C: 3-{4-[(3-methoxypropyl)amino]-1,2,5- Diazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4- Diazol-5(4 H )-one

使用2,2,2-三氟-N -(4-{5-側氧基-4-[3-(三氟甲基)苯基]-4,5-二氫-1,2,4-二唑-3-基}-1,2,5-二唑-3-基)乙醯胺作為起始物質、根據實例3步驟C 之程序製備所要化合物(49%產率)。C15 H15 F3 N5 O4 (M+H)+ 之LCMS：m/z=386.1。Using 2,2,2-trifluoro- N- (4-{5-o-oxy-4-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1,2,4- Diazol-3-yl}-1,2,5- The desired compound (49% yield) was prepared according to the procedure of Example 3 Step C. C 15 H 15 F 3 N 5 O 4 (M + H) + The LCMS: m / z = 386.1.

1 H NMR(300 MHz,CDCl3 )：δ7.83(d,J =8.1 Hz,1 H),7.72-7.67(m,2 H),7.59(d,J =7.5 Hz,1 H),6.08-6.04(m,1 H),3.57(t,J =5.6 Hz,2 H),3.54-3.47(m,2 H),3.40(s,3 H),2.01-1.93(m,2 H)。 1 H NMR (300 MHz, CDCl 3 ): δ 7.83 (d, J = 8.1 Hz, 1 H), 7.72-7.67 (m, 2 H), 7.59 (d, J = 7.5 Hz, 1 H), 6.08 -6.04 (m, 1 H), 3.57 (t, J = 5.6 Hz, 2 H), 3.54-3.47 (m, 2 H), 3.40 (s, 3 H), 2.01-1.93 (m, 2 H).

步驟D：3-{4-[(3-羥基丙基)胺基]-1,2,5-二唑-3-基}-4-[3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮Step D: 3-{4-[(3-hydroxypropyl)amino]-1,2,5- Diazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4- Diazol-5(4 H )-one

使用3-{4-[(3-甲氧基丙基)胺基]-1,2,5-二唑-3-基}-4-[3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮作為起始物質、根據實例3步驟D 之程序製備所要化合物(69%產率)。C14 H13 F3 N5 O4 (M+H)+ 之LCMS：m/z=372.1。1 H NMR(400 MHz,DMSO-d 6 )：δ8.07(s,1 H),7.95-7.90(m,2 H),7.79(dd,J =7.9,7.9 Hz,1 H),6.55(t,J =5.6 Hz,1 H),4.59(t,J =5.1 Hz,1 H),3.47-3.42(m,2 H),3.30-3.25(m,2 H),1.72-1.65(m,2 H)。Using 3-{4-[(3-methoxypropyl)amino]-1,2,5- Diazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4- Oxadiazol -5 (4 H) - one as a starting material, the desired compound (69% yield) was prepared according to the procedure of Example 3, Step D. C 14 H 13 F 3 N 5 O 4 (M + H) + The LCMS: m / z = 372.1. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.07 (s, 1 H), 7.95-7.90 (m, 2 H), 7.79 (dd, J = 7.9, 7.9 Hz, 1 H), 6.55 ( t, J = 5.6 Hz, 1 H), 4.59 (t, J = 5.1 Hz, 1 H), 3.47-3.42 (m, 2 H), 3.30-3.25 (m, 2 H), 1.72-1.65 (m, 2 H).

步驟E：3-{4-[(3-疊氮基丙基)胺基]-1,2,5-二唑-3-基}-4-[3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮Step E: 3-{4-[(3-azidopropyl)amino]-1,2,5- Diazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4- Diazol-5(4 H )-one

使用3-{4-[(3-羥基丙基)胺基]-1,2,5-二唑-3-基}-4-[3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮作為起始物質、根據實例3步驟E 之程序製備所要化合物(92%產率)。C14 H11 F3 N8 O3 Na(M+Na)+ 之LCMS：m/z=419.0。Using 3-{4-[(3-hydroxypropyl)amino]-1,2,5- Diazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4- Oxadiazol -5 (4 H) - one as a starting material, according to the procedure of Example 3, Step E Preparation of desired compound (92% yield). C 14 H 11 F 3 N 8 O 3 Na (M + Na) + The LCMS: m / z = 419.0.

步驟F：3-{4-[(3-胺基丙基)胺基]-1,2,5-二唑-3-基}-4-[3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮氫碘酸鹽Step F: 3-{4-[(3-Aminopropyl)amino]-1,2,5- Diazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4- Diazol-5(4 H )-one hydroiodide

使用3-{4-[(3-疊氮基丙基)胺基]-1,2,5-二唑-3-基}-4-[3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮作為起始物質、根據實例3步驟F 之程序製備所要化合物(92%產率)。C14 H14 F3 N6 O3 (M+H)+ 之LCMS：m/z=371.1。1 H NMR(400 MHz,DMSO-d 6 )：δ8.09(s,1 H),7.96-7.92(m,2 H),7.80(dd,J =8.0,7.8 Hz,1 H),7.53(br s,2 H),6.70-6.65(m,1 H),4.10(br s,1 H),3.32-3.31(m,2 H),2.81-2.78(m,2 H),1.85-1.82(m,2 H)。Using 3-{4-[(3-azidopropyl)amino]-1,2,5- Diazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4- Oxadiazol -5 (4 H) - one as a starting material, according to the procedure of Example 3, Step F for preparing the desired compound (92% yield). C 14 H 14 F 3 N 6 O 3 (M + H) + The LCMS: m / z = 371.1. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.09 (s, 1 H), 7.96-7.92 (m, 2 H), 7.80 (dd, J = 8.0, 7.8 Hz, 1 H), 7. Br s, 2 H), 6.70-6.65 (m, 1 H), 4.10 (br s, 1 H), 3.32-3.31 (m, 2 H), 2.81-2.78 (m, 2 H), 1.85-1.82 ( m, 2 H).

步驟G：4-({3-[(胺基磺醯基)胺基]丙基}胺基)-N' -羥基-N -[3-(三氟甲基)苯基]-1,2,5-二唑-3-甲醯亞胺醯胺Step G: 4 - ({3 - [( acyl group sulfo) amino] propyl} amino) - N '- hydroxy - N - [3- (trifluoromethyl) phenyl] -1,2 , 5- Diazole-3-carboxamide

將3-{4-[(3-胺基丙基)胺基]-1,2,5-二唑-3-基}-4-[3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮氫碘酸鹽(1.5 g，3.0 mmol)及磺醯胺(1.7 g，18 mmol)於吡啶(60 mL)中之溶液在微波中、在130℃下加熱10分鐘。濃縮反應混合物以產生粗中間物N -{3-[(4-{5-側氧基-4-[3-(三氟甲基)苯基]-4,5-二氫-1,2,4-二唑-3-基}-1,2,5-二唑-3-基)胺基]丙基}磺醯胺。以2 N NaOH(12 mL，24 mmol)處理粗中間物於甲醇(90 mL)中之溶液且在25℃下攪拌30分鐘。以6 M HCl處理反應混合物直至溶液呈酸性，且以乙酸乙酯(250 mL)萃取。以水(100 mL)及鹽水(100 mL)洗滌有機層，經無水硫酸鈉乾燥，過濾且濃縮以產生粗殘餘物。藉由製備型HPLC純化此物質，以產生呈膠黏固體狀之所要產物(1.1 g，82%)。C13 H17 F3 N7 O4 S(M+H)+ 之LCMS：m/z=424.0。1 H NMR(400 MHz,DMSO-d 6 )：δ11.6(s,1 H),9.12(s,1 H),7.37(dd,J =8.0,8.0 Hz,1 H),7.21-7.18(m,1 H),7.07(s,1 H),6.95(d,J =10.0 Hz,1 H),6.52(br s,3 H),6.17(t,J =6.0 Hz,1 H),3.28-3.22(m,2 H),2.93-2.89(m,2 H),1.77-1.73(m,2 H)。3-{4-[(3-Aminopropyl)amino]-1,2,5- Diazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4- A solution of oxazol-5( 4H )-one hydroiodide (1.5 g, 3.0 mmol) and sulfonamide (1.7 g, 18 mmol) in pyridine (60 mL). 10 minutes. The reaction mixture was concentrated to give the crude intermediate N- {3-[(4-{5-o-oxy-4-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1,2, 4- Diazol-3-yl}-1,2,5- Azoxa-3-yl)amino]propyl}sulfonamide. A solution of the crude intermediate in MeOH (90 mL) wasEtOAc. The reaction mixture was treated with 6 M HCl until the solution was acidic and extracted with ethyl acetate (250 mL). The organic layer was washed with water (100 mL) EtOAc. This material was purified by preparative HPLC to give the desired product (1.1 g, 82%). C 13 H 17 F 3 N 7 O 4 S (M + H) + The LCMS: m / z = 424.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 11.6 (s, 1 H), 9.12 (s, 1 H), 7.37 (dd, J = 8.0, 8.0 Hz, 1 H), 7.21-7. m, 1 H), 7.07 (s, 1 H), 6.95 (d, J = 10.0 Hz, 1 H), 6.52 (br s, 3 H), 6.17 (t, J = 6.0 Hz, 1 H), 3.28 -3.22 (m, 2 H), 2.93 - 2.89 (m, 2 H), 1.77-1.73 (m, 2 H).

實例16Example 16 N' -羰基-4-({3-[(甲基磺醯基)胺基]丙基}胺基)- N -[3-(三氟甲基)苯基]-1,2,5- 二唑-3-甲醯亞胺醯胺 N '- carbonyl-4 - ({3 - [(acyl sulfo methyl) amino] propyl} amino) - N - [3- (trifluoromethyl) phenyl] -1,2,5 Diazole-3-carboxamide

以三乙胺(17 μL，0.12 mmol)及甲烷磺醯氯(6 μL，70 μmol)處理3-{4-[(3-胺基丙基)胺基]-1,2,5-二唑-3-基}-4-[3-(三氟甲基)苯基]-1,2,4-二唑-5(4H )-酮氫碘酸鹽(來自實例15步驟F；25 mg，50 μmol)於二氯甲烷(1 mL)中之溶液且在25℃下攪拌2小時。濃縮反應混合物以產生粗殘餘物形式之中間物N -{3-[(4-{5-側氧基-4-[3-(三氟甲基)苯基]-4,5-二氫-1,2,4-二唑-3-基}-1,2,5-二唑-3-基)胺基]丙基}甲烷磺醯胺，其不經進一步純化而使用。以2 N NaOH(0.25 mL，0.5 mmol)處理粗中間物於甲醇(1 mL)中之溶液且在25℃下攪拌30分鐘。以乙酸(50 μL，0.9 mmol)處理反應混合物，過濾且藉由製備型LCMS純化以產生呈固體狀之所要產物(13 mg，65%)。C14 H18 F3 N6 O4 S(M+H)+ 之LCMS：m/z=423.1。1 H NMR(400 MHz,DMSO-d 6 )：δ11.6(s,1 H),9.11(s,1 H),7.37(dd,J =8.0,8.0 Hz,1 H),7.20(d,J =7.8 Hz,1 H),7.07-7.01(m,2 H),6.96(d,J =8.0 Hz,1 H),6.20(t,J =5.9 Hz,1 H),3.27-3.22(m,2 H),2.99-2.94(m,2 H),2.87(s,3 H),1.78-1.71(m,2 H)。Treatment of 3-{4-[(3-aminopropyl)amino]-1,2,5- with triethylamine (17 μL, 0.12 mmol) and methanesulfonium chloride (6 μL, 70 μmol) Diazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4- A solution of the oxazol-5( 4H )-one hydroperiodate (from Example 15 Step F; 25 mg, 50 μmol) in dichloromethane (1 mL). The reaction mixture was concentrated to give the intermediate N- {3-[(4-{5-p-oxy-4-[3-(trifluoromethyl)phenyl]-4,5-dihydro- 1,2,4- Diazol-3-yl}-1,2,5- Azoxa-3-yl)amino]propyl}methanesulfonamide, which was used without further purification. The solution of the crude intermediate in MeOH (1 mL) wasEtOAc. The reaction mixture was taken with EtOAc (EtOAc (EtOAc)EtOAc. C 14 H 18 F 3 N 6 O 4 S (M + H) + The LCMS: m / z = 423.1. 1 H NMR (400 MHz, DMSO- d 6 ): δ 11.6 (s, 1 H), 9.11 (s, 1 H), 7.37 (dd, J = 8.0, 8.0 Hz, 1 H), 7.20 (d, J = 7.8 Hz, 1 H), 7.07-7.01 (m, 2 H), 6.96 (d, J = 8.0 Hz, 1 H), 6.20 (t, J = 5.9 Hz, 1 H), 3.27-3.22 (m) , 2 H), 2.99-2.94 (m, 2 H), 2.87 (s, 3 H), 1.78-1.71 (m, 2 H).

實例17Example 17 N -(4-氟-3-甲基苯基)- N '-羥基-4-({2-[(甲基磺醯基)胺基]乙基}胺基)-1,2,5- 二唑-3-甲醯亞胺醯胺 N- (4-Fluoro-3-methylphenyl) -N '-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5- Diazole-3-carboxamide

步驟A：{2-[(甲基磺醯基)胺基]乙基}胺基甲酸第三丁酯Step A: {2-[(Methylsulfonyl)amino]ethyl}aminocarboxylic acid tert-butyl ester

將N -(2-胺基乙基)(第三丁氧基)甲醯胺(17.5 mL，0.11 mol)[Alfa #L19947]在二氯甲烷(320 mL)中攪拌且添加三乙胺(33 mL，0.24 mol)。添加甲烷磺醯氯(8.5 mL，0.11 mol)於二氯甲烷(10 mL)中之溶液。將所得混合物攪拌1小時且添加水(30 mL)。以二氯甲烷(3×30 mL)萃取產物，經硫酸鈉乾燥且真空濃縮以產生所要產物(21 g，81%)。C3 H11 N2 O2 S(M-Boc+H)+ 之LCMS計算值：m/z=139.1。 N- (2-Aminoethyl)(t-butoxy)carbamamine (17.5 mL, 0.11 mol) [Alfa #L19947] was stirred in dichloromethane (320 mL) and triethylamine (33) mL, 0.24 mol). A solution of methanesulfonium chloride (8.5 mL, 0.11 mol) in dichloromethane (10 mL) was added. The resulting mixture was stirred for 1 hour and water (30 mL) was added. The product was extracted with EtOAc (EtOAc m. C 3 H 11 N 2 O 2 S (M-Boc + H) + The LCMS calc: m / z = 139.1.

步驟B：N -(2-胺基乙基)甲烷磺醯胺二鹽酸鹽Step B: N- (2-Aminoethyl)methanesulfonamide dihydrochloride

將{2-[(甲基磺醯基)胺基]乙基}胺基甲酸第三丁酯(21 g，88 mmol)在4 N氯化氫於1,4-二烷(97 mL，388 mmol)中之溶液中攪拌30分鐘。以乙酸乙酯及己烷濕磨且隨後以***及己烷濕磨，產生呈膠狀之所要化合物(19 g，100%)。C3 H11 N2 O2 S(M+H)+ 之LCMS計算值：m/z=139.0。Tert-butyl {2-[(methylsulfonyl)amino]ethyl}aminocarbamate (21 g, 88 mmol) in 4 N hydrogen chloride over 1,4- The solution in alkane (97 mL, 388 mmol) was stirred for 30 min. It was triturated with ethyl acetate and hexanes and then triturated with diethyl ether and hexane to give the desired compound (19 g, 100%). C 3 H 11 N 2 O 2 S (M + H) + The LCMS calc: m / z = 139.0.

步驟C：4-胺基-N' -羥基-N -{2-[(甲基磺醯基)胺基]乙基}-1,2,5-二唑-3-甲醯亞胺醯胺Step C: 4-Amino- N' -hydroxy- N- {2-[(methylsulfonyl)amino]ethyl}-1,2,5- Diazole-3-carboxamide

在乙醇(460 mL)中攪拌4-胺基-N -羥基-1,2,5-二唑-3-甲醯亞胺醯氯(9.7 g，60 mmol)且緩慢數份添加N -(2-胺基乙基)甲烷磺醯胺二鹽酸鹽(19 g，109 mmol)且使溫度升至25℃。在冷卻回至0℃後，經15分鐘逐滴添加三乙胺(53 mL，380 mmol)且將反應物再攪拌15分鐘。以水(300 mL)及鹽水(300 mL)洗滌溶液。經硫酸鈉乾燥有機層且真空濃縮以產生所要產物(16 g，100%)。C6 H13 N6 O4 S(M+H)+ 之LCMS計算值：m/z=265.1。1 H NMR(400 MHz,DMSO-d 6 )：δ10.16(s,1H),9.07(m,1H),7.18(m,1H),6.37(s,2H),3.36(m,2H),3.15(m,2H),2.87(s,3H)。Stirring 4-amino- N -hydroxy-1,2,5- in ethanol (460 mL) Diazole-3-carboximine ruthenium chloride (9.7 g, 60 mmol) and slowly added N- (2-aminoethyl)methanesulfonamide dihydrochloride (19 g, 109 mmol) in portions and The temperature rose to 25 °C. After cooling back to 0 °C, triethylamine (53 mL, 380 mmol) was added dropwise over 15 min and the mixture was stirred for 15 min. The solution was washed with water (300 mL) and brine (300 mL). The organic layer was dried <RTI ID=0.0> LCMS calcd for C 6 H 13 N 6 O 4 S (M+H) + : m/z = 265.1. 1 H NMR (400 MHz, DMSO- d 6 ): δ 10.16 (s, 1H), 9.07 (m, 1H), 7.18 (m, 1H), 6.37 (s, 2H), 3.36 (m, 2H), 3.15 (m, 2H), 2.87 (s, 3H).

步驟D：N '-羥基-4-({2-[(甲基磺醯基)胺基]乙基}胺基)-1,2,5-二唑-3-甲醯亞胺醯胺Step D: N '- hydroxy-4 - ({2 - [(acyl sulfo methyl) amino] ethyl} amino) -1,2,5 Diazole-3-carboxamide

在1,2-乙二醇(38 mL)中攪拌4-胺基-N '-羥基-N -{2-[(甲基磺醯基)胺基]乙基}-1,2,5-二唑-3-甲醯亞胺醯胺(0.47 g，1.8 mmol)。以一份添加氫氧化鉀(600 g，11 mmol)。將反應物在130℃下加熱4小時且使其冷卻至室溫。添加1 N HCl溶液(60 mL)且以乙酸乙酯(4×40 mL)萃取產物。經硫酸鈉乾燥經合併之有機物且真空濃縮以產生所要產物(0.45 g，96%)。C6 H12 N6 O4 S(M+H)+ 之LCMS計算值：m/z=265.1。1 H NMR(400 MHz,DMSO-d 6 )：δ10.49(s,1H),7.18(m,1H),6.20(m,3H),3.36(m,2H),3.15(m,2H),2.87(s,3H)。Stirring 4-amino- N '-hydroxy- N -{2-[(methylsulfonyl)amino]ethyl}-1,2,5- in 1,2-ethanediol (38 mL) Diazole-3-carboximine decylamine (0.47 g, 1.8 mmol). Add potassium hydroxide (600 g, 11 mmol) in one portion. The reaction was heated at 130 °C for 4 hours and allowed to cool to room temperature. 1 N HCl solution (60 mL) was added and the product was extracted ethyl acetate (4×40 mL). The combined organics were dried with EtOAc (EtOAc m. C 6 H 12 N 6 O 4 S (M + H) + The LCMS calc: m / z = 265.1. 1 H NMR (400 MHz, DMSO- d 6 ): δ 10.49 (s, 1H), 7.18 (m, 1H), 6.20 (m, 3H), 3.36 (m, 2H), 3.15 (m, 2H), 2.87 (s, 3H).

步驟E：N -(4-氟-3-甲基苯基)-N' -羥基-4-({2-[(甲基磺醯基)胺基]乙基}胺基)-1,2,5-二唑-3-甲醯亞胺醯胺Step E: N- (4-Fluoro-3-methylphenyl) -N' -hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2 , 5- Diazole-3-carboxamide

在1,4-二烷(2 mL)中攪拌N '-羥基-4-({2-[(甲基磺醯基)胺基]乙基}胺基)-1,2,5-二唑-3-甲醯亞胺醯胺(35 mg，0.13 mmol)且添加6 N氯化氫溶液(4 mL)。將溶液冷卻至0℃且緩慢添加亞硝酸鈉(11 mg，0.16 mmol)於水(3 mL)中之溶液。將混合物在0℃下攪拌1小時且蒸發。添加無水1,4-二烷(2 mL)且將混合物再蒸發兩次。添加4-氟-3-甲基苯胺[Aldrich，產品號559415](25 mg，0.20 mmol)於乙醇(2 mL)中之溶液且將混合物攪拌1小時。藉由製備型LCMS(pH 2)純化產生所要化合物(17 mg，27%)。C13 H18 FN6 O4 S(M+H)+ 之LCMS計算值：m/z=373.1。1 H NMR(400 MHz,DMSO-d 6 )：δ11.25(s,1H),8.61(s,1H),7.18(m,1H),6.91(m,1H),6.72(m,1H),6.58(m,1H),6.24(s,1H),3.32(m,2H),3.11(m,2H),2.89(s,3H),2.05(s,3H)。In 1,4-two Stirring N '-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5- in alkane (2 mL) Diazole-3-carboximine amide (35 mg, 0.13 mmol) and 6 N hydrogen chloride solution (4 mL). The solution was cooled to 0 ° C and a solution of sodium nitrite (11 mg, 0.16 mmol) in water (3 mL) was slowly added. The mixture was stirred at 0 ° C for 1 hour and evaporated. Add anhydrous 1,4-two Alkane (2 mL) and the mixture was evaporated twice more. A solution of 4-fluoro-3-methylaniline [Aldrich, product number 559415] (25 mg, 0.20 mmol) in EtOAc (2 mL). Purification by preparative LCMS (pH 2) gave the desired compound (17 mg, 27%). C 13 H (M + H) + LCMS calcd of 18 FN 6 O 4 S: m / z = 373.1. 1 H NMR (400 MHz, DMSO- d 6 ): δ 11.25 (s, 1H), 8.61 (s, 1H), 7.18 (m, 1H), 6.91 (m, 1H), 6.72 (m, 1H), 6.58 (m, 1H), 6.24 (s, 1H), 3.32 (m, 2H), 3.11 (m, 2H), 2.89 (s, 3H), 2.05 (s, 3H).

實例18Example 18 4-({2-[(胺基磺醯基)胺基]乙基}胺基)- N -(3-氰基-4-氟苯基)- N' -羥基-1,2,5- 二唑-3-甲醯亞胺醯胺 4 - ({2 - [(sulfo amino acyl) amino] ethyl} amino) - N - (3- cyano-4-fluorophenyl) - N '- hydroxy-1,2,5 Diazole-3-carboxamide

步驟A：N -(3-氰基-4-氟苯基)-N' -羥基-4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯胺Step A: N - (3- cyano-4-fluorophenyl) - N '- hydroxy-4 - [(2-methoxyethyl) amino] -1,2,5 Diazole-3-carboxamide

使用N -羥基-4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯氯[根據實例1步驟A至E 製備]及5-胺基-2-氟苯甲腈[Aldrich，產品號639877]作為起始物質、根據實例13步驟A 之程序製備所要化合物(100%產率)。C13 H14 FN6 O3 (M+H)+ 之LCMS：m/z=321.0。Using N -hydroxy-4-[(2-methoxyethyl)amino]-1,2,5- Diazole-3-carboximine oxime chloride [prepared according to Example 1 Steps A to E ] and 5-amino-2-fluorobenzonitrile [Aldrich, product number 639877] as starting material, according to Example 13 Step A Procedure The desired compound (100% yield) was prepared. C 13 H 14 FN 6 O 3 (M + H) + The LCMS: m / z = 321.0.

步驟B：2-氟-5-[3-{4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-基}-5-側氧基-1,2,4-二唑-4(5H )-基]苯甲腈Step B: 2-Fluoro-5-[3-{4-[(2-methoxyethyl)amino]-1,2,5- Diazol-3-yl}-5-sideoxy-1,2,4- Diazol-4(5 H )-yl]benzonitrile

使用N -(3-氰基-4-氟苯基)-N' -羥基-4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯胺作為起始物質、根據實例13步驟B 之程序製備所要化合物(91%產率)。C14 H12 FN6 O4 (M+H)+ 之LCMS：m/z=347.0。1 H NMR(400 MHz,DMSO-d 6 )：δ8.25(dd,J =5.7,2.6 Hz,1 H),8.06(m,1 H),7.77(t,J =9.2 Hz,1 H),6.41(t,J =5.7 Hz,1 H),3.48(m,2 H),3.40(q,J =5.4 Hz,2 H),3.25(s,3 H)。Using N - (3- cyano-4-fluorophenyl) - N '- hydroxy-4 - [(2-methoxyethyl) amino] -1,2,5 The desired compound (91% yield) was prepared according to the procedure from Example 13 Step B. C 14 H 12 FN 6 O 4 (M + H) + The LCMS: m / z = 347.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.25 (dd, J = 5.7, 2.6 Hz, 1 H), 8.06 (m, 1 H), 7.77 (t, J = 9.2 Hz, 1 H) , 6.41 (t, J = 5.7 Hz, 1 H), 3.48 (m, 2 H), 3.40 (q, J = 5.4 Hz, 2 H), 3.25 (s, 3 H).

步驟C：2-氟-5-[3-{4-[(2-羥基乙基)胺基]-1,2,5-二唑-3-基}-5-側氧基-1,2,4-二唑-4(5H )-基]苯甲腈Step C: 2-Fluoro-5-[3-{4-[(2-hydroxyethyl)amino]-1,2,5- Diazol-3-yl}-5-sideoxy-1,2,4- Diazol-4(5 H )-yl]benzonitrile

使用2-氟-5-[3-{4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-基}-5-側氧基-1,2,4-二唑-4(5H )-基]苯甲腈作為起始物質、根據實例13步驟C 之程序製備所要化合物(定量產量)。C13 H10 FN6 O4 (M+H)+ 之LCMS：m/z=333.0。Using 2-fluoro-5-[3-{4-[(2-methoxyethyl)amino]-1,2,5- Diazol-3-yl}-5-sideoxy-1,2,4- The desired compound (quantitative yield) was prepared according to the procedure of Example 13 Step C using oxazol-4( 5H )-yl]benzonitrile as starting material. C 13 H 10 FN 6 O 4 (M + H) + The LCMS: m / z = 333.0.

步驟D：甲烷磺酸2-({4-[4-(3-氰基-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}胺基)乙酯Step D: 2-({4-[4-(3-Cyano-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4- methanesulfonic acid) Diazol-3-yl]-1,2,5- Diazol-3-yl}amino)ethyl ester

使用2-氟-5-[3-{4-[(2-羥基乙基)胺基]-1,2,5-二唑-3-基}-5-側氧基-1,2,4-二唑-4(5H )-基]苯甲腈作為起始物質、根據實例13步驟D 之程序製備所要化合物(88%產率)。C14 H12 FN6 O6 S(M+H)+ 之LCMS：m/z=411.0。Using 2-fluoro-5-[3-{4-[(2-hydroxyethyl)amino]-1,2,5- Diazol-3-yl}-5-sideoxy-1,2,4- Oxadiazole -4 (5 H) - yl] -benzonitrile as starting materials, according to the procedure of Example 13, Step D Preparation of desired compound (88% yield). C 14 H 12 FN 6 O 6 S (M + H) + The LCMS: m / z = 411.0.

步驟E：5-[3-{4-[(2-疊氮基乙基)胺基]-1,2,5-二唑-3-基}-5-側氧基-1,2,4-二唑-4(5H )-基]-2-氟苯甲腈Step E: 5-[3-{4-[(2-azidoethyl)amino]-1,2,5- Diazol-3-yl}-5-sideoxy-1,2,4- Oxadiazole -4 (5 H) - yl] -2-fluorobenzonitrile

使用甲烷磺酸2-({4-[4-(3-氰基-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}胺基)乙酯作為起始物質、根據實例13步驟E 之程序製備所要化合物(95%產率)。2-({4-[4-(3-Cyano-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4- using methanesulfonic acid Diazol-3-yl]-1,2,5- The desired compound (95% yield) was prepared according to the procedure of Example 13 Step E.

步驟F：5-[3-{4-[(2-胺基乙基)胺基]-1,2,5-二唑-3-基}-5-側氧基-1,2,4-二唑-4(5H )-基]-2-氟苯甲腈氫碘酸鹽Step F: 5-[3-{4-[(2-Aminoethyl)amino]-1,2,5- Diazol-3-yl}-5-sideoxy-1,2,4- Diazol-4( 5H )-yl]-2-fluorobenzonitrile hydroiodide

使用5-[3-{4-[(2-疊氮基乙基)胺基]-1,2,5-二唑-3-基}-5-側氧基-1,2,4-二唑-4(5H )-基]-2-氟苯甲腈作為起始物質、根據實例13步驟F 之程序製備所要化合物(57%產率)。C13 H11 FN7 O3 (M+H)+ 之LCMS：m/z=332.0。1 H NMR(400 MHz,DMSO-d 6 )：δ8.29(dd,J =5.8,2.7 Hz,1 H),8.09(m,1 H),7.83(br s,3 H),7.79(t,J =9.0 Hz,1 H),6.77(t,J =5.9 Hz,1 H),3.50(q,J =6.4 Hz,2 H),3.04(m,2 H)。5-[3-{4-[(2-azidoethyl)amino]-1,2,5- Diazol-3-yl}-5-sideoxy-1,2,4- The desired compound (57% yield) was prepared according to the procedure of step 13 of Example 13 using oxazol-4( 5H )-yl]-2-fluorobenzonitrile as starting material. C 13 H 11 FN 7 O 3 (M + H) + The LCMS: m / z = 332.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.29 (dd, J = 5.8, 2.7 Hz, 1 H), 8.09 (m, 1 H), 7.83 (br s, 3 H), 7.79 (t , J = 9.0 Hz, 1 H), 6.77 (t, J = 5.9 Hz, 1 H), 3.50 (q, J = 6.4 Hz, 2 H), 3.04 (m, 2 H).

步驟G：4-({2-[(胺基磺醯基)胺基]乙基}胺基)-N -(3-氰基-4-氟苯基)-N' -羥基-1,2,5-二唑-3-甲醯亞胺醯胺Step G: 4 - ({2 - [( sulfo amino acyl) amino] ethyl} amino) - N - (3- cyano-4-fluorophenyl) - N '- hydroxy-1,2 , 5- Diazole-3-carboxamide

在微波小瓶中，將5-[3-{4-[(2-胺基乙基)胺基]-1,2,5-二唑-3-基}-5-側氧基-1,2,4-二唑-4(5H )-基]-2-氟苯甲腈氫碘酸鹽(20.0 mg，0.044 mmol)及磺醯胺(25 mg，0.26 mmol)懸浮於吡啶(0.5 mL)中。將反應物在微波反應器中加熱至120℃歷時10分鐘。移除溶劑且將殘餘物溶解於甲醇(0.17 mL)中。以一份添加2.0 N NaOH於水中之溶液(0.22 mL，0.44 mmol)。將反應物在室溫下攪拌隔夜。以乙酸(50 μL)中和後，使用製備型LCMS純化產物以產生標題化合物(4.9 mg，29%)。C12 H14 FN8 O4 S(M+H)+ 之LCMS：m/z=385.0。1 H NMR(400 MHz,DMSO-d 6 )：δ11.65(s,1H),9.08(s,1H),7.34(t,J =9.1 Hz,1H),7.22(dd,J =5.4,2.8 Hz,1H),7.13(m,1H),6.70(t,J =5.9 Hz,1H),6.59(s,2H),6.20(t,J =6.1 Hz,1H),3.34(m,2H),3.09(m,2H)。In a microwave vial, 5-[3-{4-[(2-aminoethyl)amino]-1,2,5- Diazol-3-yl}-5-sideoxy-1,2,4- The oxazol-4( 5H )-yl]-2-fluorobenzonitrile hydroiodide (20.0 mg, 0.044 mmol) and sulfonamide (25 mg, 0.26 mmol) were suspended in pyridine (0.5 mL). The reaction was heated to 120 °C in a microwave reactor for 10 minutes. The solvent was removed and the residue was dissolved in methanol (0.17 mL). A solution of 2.0 N NaOH in water (0.22 mL, 0.44 mmol) was added. The reaction was stirred at room temperature overnight. After neutralization with acetic acid (50 [mu]L), the product was purified using EtOAc (EtOAc) C 12 H 14 FN 8 O 4 S (M + H) + The LCMS: m / z = 385.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 11.65 (s, 1H), 9.08 (s, 1H), 7.34 (t, J = 9.1 Hz, 1H), 7.22 (dd, J = 5.4, 2.8 Hz, 1H), 7.13 (m, 1H), 6.70 (t, J = 5.9 Hz, 1H), 6.59 (s, 2H), 6.20 (t, J = 6.1 Hz, 1H), 3.34 (m, 2H), 3.09 (m, 2H).

實例19Example 19 N -(3-氰基-4-氟苯基)- N' -羥基-4-({2-[(甲基磺醯基)胺基]乙基}胺基)-1,2,5- 二唑-3-甲醯亞胺醯胺 N - (3- cyano-4-fluorophenyl) - N '- hydroxy-4 - ({2 - [(acyl sulfo methyl) amino] ethyl} amino) -1,2,5 Diazole-3-carboxamide

使用N '-羥基-4-({2-[(甲基磺醯基)胺基]乙基}胺基)-1,2,5-二唑-3-甲醯亞胺醯胺及3-氰基-4-氟苯胺[Aldrich，產品號639877]作為起始物質、根據實例17步驟E 之程序製備標題化合物。C13 H14 FN7 NaO4 S(M+Na)+ 之LCMS：m/z=406.0。1 H NMR(400 MHz,DMSO-d 6 )：δ11.65(s,1H),9.08(s,1H),7.35(m,1H),7.18(m,3H),6.56(m,1H),6.23(m,1H),6.24(s,2H),3.32(m,2H),3.14(m,2H),2.89(s,3H)。Using N '-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5- The title compound was prepared according to the procedure of Example 17 Step E. m. m. C 13 H 14 FN 7 NaO 4 S (M + Na) + The LCMS: m / z = 406.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 11.65 (s, 1H), 9.08 (s, 1H), 7.35 (m, 1H), 7.18 (m, 3H), 6.56 (m, 1H), 6.23 (m, 1H), 6.24 (s, 2H), 3.32 (m, 2H), 3.14 (m, 2H), 2.89 (s, 3H).

實例20Example 20 4-({2-[(胺基磺醯基)胺基]乙基}胺基)- N -[(4--溴-2-呋喃基)甲基]- N' -羥基-1,2,5- 二唑-3-甲醯亞胺醯胺 4 - ({2 - [(sulfo amino acyl) amino] ethyl} amino) - N - [(4---bromo-2-furanyl) methyl] - N '- hydroxy-1,2 , 5- Diazole-3-carboxamide

步驟A：[(4-溴-2-呋喃基)甲基]胺基甲酸第三丁酯Step A: [(4-Bromo-2-furyl)methyl]aminocarboxylic acid tert-butyl ester

將4-溴-2-糠醛[Aldrich，產品號666599](10.0 g，57.1 mmol)溶解於乙醇(50 mL)及水(50 mL)中。依序添加N -羥基胺鹽酸鹽(7.15 g，103 mmol)及乙酸鈉(8.44 g，103 mmol)且使反應混合物在100℃下回流1小時。部分濃縮溶液且收集沈澱物且以冷水(2×10 mL)洗滌。以乙酸乙酯(3×25 mL)萃取濾液且以鹽水(50 mL)洗滌經合併之有機層。經硫酸鈉乾燥後，真空濃縮溶液。將殘餘物與沈澱物合併且溶解於乙酸(70 mL)中。置於冰浴中之後，經25分鐘逐份添加鋅(14.7 g，225 mmol)。將反應物經1.5小時溫至室溫且經矽藻土過濾。真空移除溶劑。4-Bromo-2-furaldehyde [Aldrich, product number 666599] (10.0 g, 57.1 mmol) was dissolved in ethanol (50 mL) and water (50 mL). N -Hydroxylamine hydrochloride (7.15 g, 103 mmol) and sodium acetate (8.44 g, 103 mmol) were sequentially added and the mixture was refluxed at 100 ° C for 1 hour. The solution was partially concentrated and the precipitate was collected and washed with cold water (2×10 mL). The filtrate was extracted with EtOAc (3×25 mL) andEtOAc. After drying over sodium sulfate, the solution was concentrated in vacuo. The residue was combined with a precipitate and dissolved in acetic acid (70 mL). After being placed in an ice bath, zinc (14.7 g, 225 mmol) was added portionwise over 25 minutes. The reaction was warmed to room temperature over 1.5 h and filtered over Celite. The solvent was removed in vacuo.

將殘餘物在四氫呋喃(72 mL)中攪拌。經45分鐘逐滴添加2.0 N NaOH於水中之溶液(179 mL，358 mmol)。5分鐘後，逐滴添加二碳酸二-第三丁酯(16.9 g，77.4 mmol)。將反應物攪拌2小時且真空移除四氫呋喃。添加乙酸乙酯(100 mL)且過濾懸浮液。收集有機層且以乙酸乙酯(2×50 mL)萃取產物。以鹽水(100 mL)及水(100 mL)洗滌經合併之有機層，經硫酸鈉乾燥且真空濃縮以產生所要產物(15.3 g，79%)。C10 H14 BrNNaO3 (M+Na)+ 之LCMS計算值：m/z=298.0。1 H NMR(400 MHz,DMSO-d 6 )：δ7.79(s,1 H),7.37(t,J =5.8 Hz,1 H),6.33(s,1 H),4.06(d,J =6.1 Hz,2 H),1.36(s,9 H)。The residue was stirred in tetrahydrofuran (72 mL). A solution of 2.0 N NaOH in water (179 mL, 358 mmol) was added dropwise over 45 min. After 5 minutes, di-tert-butyl dicarbonate (16.9 g, 77.4 mmol) was added dropwise. The reaction was stirred for 2 hours and tetrahydrofuran was removed in vacuo. Ethyl acetate (100 mL) was added and the suspension was filtered. The organic layer was collected and the product was extracted ethyl acetate (2×50 mL). The combined organic layers were washed with EtOAc EtOAc m. C 10 H 14 BrNNaO 3 (M + Na) + The LCMS calc: m / z = 298.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 7.79 (s, 1 H), 7.37 (t, J = 5.8 Hz, 1 H), 6.33 (s, 1 H), 4.06 (d, J = 6.1 Hz, 2 H), 1.36 (s, 9 H).

步驟B：1-(4-溴-2-呋喃基)甲胺三氟乙酸鹽Step B: 1-(4-Bromo-2-furyl)methylamine trifluoroacetate

在氮氣氛圍下，在0℃下經15分鐘以三氟乙酸(43 mL)處理[(4-溴-2-呋喃基)甲基]胺基甲酸第三丁酯(15.3 g，55.4 mmol)於二氯甲烷(86 mL)中之溶液。經30分鐘將反應混合物溫至室溫。真空移除溶劑且追加甲苯(3×50 mL)。將產物凍乾18小時以產生呈棕色固體狀之所要產物(13.0 g，81%)。C5 H4 BrO(M-NH2 )+ 之LCMS計算值：m/z=158.9,160.9。1 H NMR(400 MHz,DMSO-d 6 )：δ8.34(br s,3 H),8.01(s,1 H),6.70(s,1 H),4.08(s,1 H)。Treatment of [(4-bromo-2-furyl)methyl]carbamic acid tert-butyl ester (15.3 g, 55.4 mmol) in trifluoroacetic acid (43 mL) over 15 min. Solution in dichloromethane (86 mL). The reaction mixture was warmed to room temperature over 30 minutes. The solvent was removed in vacuo and toluene (3×50 mL) was added. The product was lyophilized for 18 hours to give the desired product (13.0 g, 81%). C 5 H 4 BrO (M- NH 2) + sum LCMS calc: m / z = 158.9,160.9. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.34 (br s, 3 H), 8. s (s, 1 H), 6.70 (s, 1 H), 4.08 (s, 1 H).

步驟C：N-[(4-溴-2-呋喃基)甲基]-N'-羥基-4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯胺Step C: N-[(4-Bromo-2-furyl)methyl]-N'-hydroxy-4-[(2-methoxyethyl)amino]-1,2,5- Diazole-3-carboxamide

在室溫下，在乙醇(20 mL)中攪拌N -羥基-4-(2-甲氧基乙基胺基)-1,2,5-二唑-3-伸亞胺醯氯[根據實例1步驟A至E 之程序製備](4.5 g，20.3 mmol)。向其中添加1-(4-溴-2-呋喃基)甲胺三氟乙酸鹽(6.5 g，22.4 mmol)於乙醇(24 mL)中之溶液且將混合物攪拌15分鐘。經10分鐘逐滴添加三乙胺(6.3 mL，44.8 mmol)且將反應物再攪拌15分鐘。真空移除溶劑且添加水(50 mL)之後，以乙酸乙酯(3×50 mL)萃取產物。以鹽水(50 mL)洗滌經合併之有機層，經硫酸鈉乾燥且真空濃縮以產生所要產物(7.5 g，100%)。C11 H15 BrN5 O4 (M+H)+ 之LCMS計算值：m/z=359.9,361.9。Stir N -Hydroxy-4-(2-methoxyethylamino)-1,2,5- in ethanol (20 mL) at room temperature Diazole-3-imine oxime chloride [prepared according to the procedure of Example 1 Steps A to E ] (4.5 g, 20.3 mmol). A solution of 1-(4-bromo-2-furanyl)methylamine trifluoroacetate (6.5 g, 22.4 mmol) in ethanol (24 mL) was added and the mixture was stirred for 15 min. Triethylamine (6.3 mL, 44.8 mmol) was added dropwise over 10 min and the reaction was stirred further 15 min. The solvent was removed in vacuo and water (50 mL) was evaporated. The combined organic layers were washed with EtOAc EtOAc m. (M + H) + The LCMS calcd C 11 H 15 BrN 5 O 4 : m / z = 359.9,361.9.

步驟D：4-[(4-溴-2-呋喃基)甲基]-3-{4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H)-酮Step D: 4-[(4-Bromo-2-furyl)methyl]-3-{4-[(2-methoxyethyl)amino]-1,2,5- Diazol-3-yl}-1,2,4- Diazol-5(4H)-one

將N -[(4-溴-2-呋喃基)甲基]-N' -羥基-4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯胺(7.3 g，20.4 mmol)及1,1'-羰基二咪唑(5.0 g，30.5 mmol)溶解於乙酸乙酯(72 mL)中。將反應混合物在65℃下加熱15分鐘。添加乙酸乙酯(70 mL)且以水(2×70 mL)中之0.1 N氯化氫洗滌粗反應物。經硫酸鈉乾燥有機層且真空中濃縮。藉由矽膠急驟層析法(使用己烷中之乙酸乙酯作為溶離劑)純化產生所要產物(4.1 g，90%)。C12 H13 BrN5 O5 (M+H)+ 之LCMS計算值：m/z=386.0,388.0。1 H NMR(400 MHz,CD3 OD)：δ7.88(s,1 H),6.67(s,1 H),6.39(t,J =5.7 Hz,1 H),5.07(s,2 H),3.50(m,2 H),3.41(q,J =5.7 Hz,2 H),3.25(s,3 H)。 N -[(4-Bromo-2-furyl)methyl] -N' -hydroxy-4-[(2-methoxyethyl)amino]-1,2,5- The oxazol-3-carboxamimidamide (7.3 g, 20.4 mmol) and 1,1'-carbonyldiimidazole (5.0 g, 30.5 mmol) were dissolved in ethyl acetate (72 mL). The reaction mixture was heated at 65 °C for 15 minutes. Ethyl acetate (70 mL) was added and the crude was washed with &lt;RTI ID=0.0&gt;&gt; The organic layer was dried over sodium sulfate and concentrated in vacuo. Purification by silica gel flash chromatography (using ethyl acetate in hexanes as solvent) afforded the desired product (4.1 g, 90%). C 12 H 13 BrN 5 O 5 (M + H) + The LCMS calc: m / z = 386.0,388.0. 1 H NMR (400 MHz, CD 3 OD): δ 7.88 (s, 1 H), 6.67 (s, 1 H), 6.39 (t, J = 5.7 Hz, 1 H), 5.07 (s, 2 H) , 3.50 (m, 2 H), 3.41 (q, J = 5.7 Hz, 2 H), 3.25 (s, 3 H).

步驟E：4-[(4-溴-2-呋喃基)甲基]-3-{4-[(2-羥基乙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H)-酮Step E: 4-[(4-Bromo-2-furyl)methyl]-3-{4-[(2-hydroxyethyl)amino]-1,2,5- Diazol-3-yl}-1,2,4- Diazol-5(4H)-one

在圓底燒瓶中，在氮氣氛圍下，在二氯甲烷(68 mL)中攪拌4-[(4-溴-2-呋喃基)甲基]-3-{4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H )-酮(8.2 g，21 mmol)。使溫度達到-78℃且經45分鐘逐滴添加1.0 M三溴化硼於二氯甲烷(43 mL，43 mmol)中之溶液。將反應物在-78℃下攪拌45分鐘且在0℃下繼續攪拌額外30分鐘。在0℃下保持的同時，經25分鐘逐滴添加碳酸氫鈉飽和水溶液(120 mL)。溫至室溫後，收集有機層且以乙酸乙酯(2×50 mL)萃取水層。以鹽水(100 mL)洗滌經合併之有機層，經硫酸鈉乾燥且真空濃縮產生所要產物(7.7 g，97%)，以及少量3-{4-[(2-溴乙基)胺基]-1,2,5-二唑-3-基}-4-[(4-溴-2-呋喃基)甲基]-1,2,4-二唑-5(4H )-酮。C11 H11 BrN5 O5 (M+H)+ 之LCMS計算值：m/z=371.7,374.0。Stirring 4-[(4-bromo-2-furyl)methyl]-3-{4-[(2-methoxy) in dichloromethane (68 mL) in a round bottom flask Ethyl)amino]-1,2,5- Diazol-3-yl}-1,2,4- Diazol-5( 4H )-one (8.2 g, 21 mmol). The temperature was brought to -78 ° C and a solution of 1.0 M boron tribromide in dichloromethane (43 mL, 43 mmol) was added dropwise over 45 min. The reaction was stirred at -78 °C for 45 minutes and stirring was continued at 0 °C for an additional 30 minutes. While maintaining at 0 ° C, a saturated aqueous solution of sodium hydrogencarbonate (120 mL) was added dropwise over 25 min. After warming to room temperature, the organic layer was collected and aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with EtOAcq EtOAc (EtOAc m. 1,2,5- Diazol-3-yl}-4-[(4-bromo-2-furyl)methyl]-1,2,4- Diazol-5(4 H )-one. C 11 H 11 BrN 5 O 5 (M + H) + The LCMS calc: m / z = 371.7,374.0.

1 H NMR(400 MHz,DMSO-d 6 )：δ7.89(s,1 H),6.68(s,1 H),6.31(t,J =5.8 Hz,1 H),5.08(s,2 H),4.85(br s,1 H),3.56(m,2 H),3.30(q,J =5.6 Hz,2 H)。 1 H NMR (400 MHz, DMSO- d 6 ): δ 7.89 (s, 1 H), 6.68 (s, 1 H), 6.31 (t, J = 5.8 Hz, 1 H), 5.08 (s, 2 H) ), 4.85 (br s, 1 H), 3.56 (m, 2 H), 3.30 (q, J = 5.6 Hz, 2 H).

步驟F：甲烷磺酸2-[(4-{4-[(4-溴-2-呋喃基)甲基]-5-側氧基-4,5-二氫-1,2,4-二唑-3-基}-1,2,5-二唑-3-基)胺基]乙酯Step F: 2-[(4-{4-[(4-Bromo-2-furyl)methyl]-5-oxo-4,5-dihydro-1,2,4-methanesulfonic acid Diazol-3-yl}-1,2,5- Diazol-3-yl)amino]ethyl ester

向4-[(4-溴-2-呋喃基)甲基]-3-{4-[(2-羥基乙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H )-酮(7.7 g，21 mmol，亦含有一些相應溴化合物)於乙酸乙酯(100 mL)中之溶液中以一份添加甲烷磺醯氯(0.96 mL，12 mmol)。將反應物攪拌5分鐘且亦以一份添加三乙胺(1.6 mL，11 mmol)。攪拌30分鐘後，添加額外甲烷磺醯氯(0.4 mL，5 mmol)，隨後在5分鐘後添加三乙胺(0.58 mL，4.2 mmol)。15分鐘後，在添加水(100 mL)下中止反應。以乙酸乙酯(3×50 mL)萃取產物且以鹽水(100 mL)洗滌經合併之有機層。經硫酸鈉乾燥後，真空移除溶劑產生所要產物(9.3 g，100%)。C12 H13 BrN5 O7 S(M+H)+ 之LCMS計算值：m/z=449.8,451.8。1 H NMR(300 MHz,DMSO-d 6 )：δ7.88(s,1 H),6.73(t,J =6.2 Hz,1 H),6.68(s,1 H),5.08(s,2 H),4.37(m,2 H),3.59(q,J =5.8 Hz,2 H),3.16(s,3 H)。To 4-[(4-bromo-2-furyl)methyl]-3-{4-[(2-hydroxyethyl)amino]-1,2,5- Diazol-3-yl}-1,2,4- Addition of methanesulfonium chloride (0.96 mL, 12 mmol) to a solution of oxazol-5( 4H )-one (7.7 g, 21 mmol, containing some corresponding bromo compound) in ethyl acetate (100 mL) ). The reaction was stirred for 5 min and triethylamine (1.6 mL, 11 mmol) was then taken in one portion. After stirring for 30 minutes, additional methanesulfonium chloride (0.4 mL, 5 mmol) was added, then triethylamine (0.58 mL, 4.2 mmol) was added after 5 min. After 15 minutes, the reaction was quenched with the addition of water (100 mL). The product was extracted with EtOAc (3×50 mL)EtOAc. After drying over sodium sulphate, the solvent was removed in vacuo to give the desired product (9.3 g, 100%). C 12 H 13 BrN 5 O 7 S (M + H) + The LCMS calc: m / z = 449.8,451.8. 1 H NMR (300 MHz, DMSO- d 6 ): δ 7.88 (s, 1 H), 6.73 (t, J = 6.2 Hz, 1 H), 6.68 (s, 1 H), 5.08 (s, 2 H) ), 4.37 (m, 2 H), 3.59 (q, J = 5.8 Hz, 2 H), 3.16 (s, 3 H).

步驟G：3-{4-[(2-疊氮基乙基)胺基]-1,2,5-二唑-3-基}-4-[(4-溴-2-呋喃基)甲基]-1,2,4-二唑-5(4H)-酮Step G: 3-{4-[(2-azidoethyl)amino]-1,2,5- Diazol-3-yl}-4-[(4-bromo-2-furyl)methyl]-1,2,4- Diazol-5(4H)-one

將甲烷磺酸2-[(4-{4-[(4-溴-2-呋喃基)甲基]-5-側氧基-4,5-二氫-1,2,4-二唑-3-基}-1,2,5-二唑-3-基)胺基]乙酯(9.1 g，20 mmol，亦含有一些相應溴化合物)溶解於二甲基甲醯胺(90 mL)中。以一份添加疊氮化鈉(1.97 g，30.3 mmol)且在5分鐘後，使溫度達到65℃。將反應物攪拌2小時且使其冷卻回至室溫。添加水(200 mL)以中止反應。以乙酸乙酯(3×100 mL)萃取產物且以鹽水(2×150 mL)及水(150 mL)洗滌經合併之有機層。經硫酸鈉乾燥後，真空移除溶劑產生所要產物(7.7 g，96%)。C11 H9 BrN8 NaO4 (M+Na)+ 之LCMS計算值：m/z=418.7,421.0。1 H NMR(400 MHz,DMSO-d 6 )：δ7.88(s,1 H),6.71(t,J =5.7 Hz,1 H),6.68(s,1 H),5.08(s,2 H),3.54(t,J =5.7 Hz,2 H),3.47(q,J =5.7 Hz,2 H)。2-[(4-{4-[(4-Bromo-2-furyl)methyl]-5-sideoxy-4,5-dihydro-1,2,4- methanesulfonate Diazol-3-yl}-1,2,5- The oxazol-3-yl)amino]ethyl ester (9.1 g, 20 mmol, also containing some corresponding bromine compound) was dissolved in dimethylformamide (90 mL). A sodium azide (1.97 g, 30.3 mmol) was added in one portion and after 5 minutes, the temperature was brought to 65 °C. The reaction was stirred for 2 hours and allowed to cool back to room temperature. Water (200 mL) was added to stop the reaction. The product was extracted with EtOAc (3×100 mL). After drying over sodium sulphate, the solvent was removed in vacuo to give the desired product (7.7 g, 96%). C 11 H 9 BrN 8 NaO 4 (M + Na) + The LCMS calc: m / z = 418.7,421.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 7.88 (s, 1 H), 6.71 (t, J = 5.7 Hz, 1 H), 6.68 (s, 1 H), 5.08 (s, 2 H) ), 3.54 (t, J = 5.7 Hz, 2 H), 3.47 (q, J = 5.7 Hz, 2 H).

步驟H：3-{4-[(2-胺基乙基)胺基]-1,2,5-二唑-3-基}-4-[(4-溴-2-呋喃基)甲基]-1,2,4-二唑-5(4H)-酮氫碘酸鹽Step H: 3-{4-[(2-Aminoethyl)amino]-1,2,5- Diazol-3-yl}-4-[(4-bromo-2-furyl)methyl]-1,2,4- Diazol-5(4H)-one hydroiodide

向3-{4-[(2-疊氮基乙基)胺基]-1,2,5-二唑-3-基}-4-[(4-溴-2-呋喃基)甲基]-1,2,4-二唑-5(4H)-酮(7.7 g，19 mmol)於甲醇(80 mL)中之溶液中添加碘化鈉(17.4 g，116 mmol)。攪拌10分鐘後，經5分鐘逐滴添加氯三甲基矽烷之溶液(14.8 mL，116 mmol)。將反應物繼續攪拌1小時，此時在0℃下將其緩慢添加至硫代硫酸鈉(23.0 g，145 mmol)於水(800 mL)中之溶液中，產生沈澱物。以甲醇(10 mL)沖洗燒瓶且經由真空過濾收集沈澱物。以冷水(2×25 mL)沖洗固體且在真空下乾燥產生作為氫碘酸鹽之所要產物(5.8 g，60%)。C11 H12 BrN6 O4 (M+H)+ 之LCMS計算值：m/z=370.9,372.8。1 H NMR(400 MHz,DMSO-d 6 )：δ7.86(s,1 H),7.36(br s,3 H),6.68(t,J =5.8 Hz,1 H),6.65(s,1 H),5.07(s,2 H),3.45(q,J =5.8 Hz,2 H),2.98(t,J =5.8 Hz,2 H)。To 3-{4-[(2-azidoethyl)amino]-1,2,5- Diazol-3-yl}-4-[(4-bromo-2-furyl)methyl]-1,2,4- Sodium iodide (17.4 g, 116 mmol) was added to a solution of oxazol-5(4H)-one (7.7 g, 19 mmol) in methanol (EtOAc). After stirring for 10 minutes, a solution of chlorotrimethyldecane (14.8 mL, 116 mmol) was added dropwise over 5 min. The reaction was stirred for a further 1 hour at which time it was slowly added to a solution of sodium thiosulfate (23.0 g, 145 mmol) in water (800 mL). The flask was rinsed with methanol (10 mL) and the precipitate was collected by vacuum filtration. The solid was washed with cold water (2 x 25 mL) and dried in vacuo to give the desired product ( 5.8 g, 60%). (M + H) + The LCMS calcd C 11 H 12 BrN 6 O 4 : m / z = 370.9,372.8. 1 H NMR (400 MHz, DMSO- d 6 ): δ 7.86 (s, 1 H), 7.36 (br s, 3 H), 6.68 (t, J = 5.8 Hz, 1 H), 6.65 (s, 1) H), 5.07 (s, 2 H), 3.45 (q, J = 5.8 Hz, 2 H), 2.98 (t, J = 5.8 Hz, 2 H).

步驟I：4-({2-[(胺基磺醯基)胺基]乙基}胺基)-N-[(4-溴-2-呋喃基)甲基]-N'-羥基-1,2,5-二唑-3-甲醯亞胺醯胺Step I: 4-({2-[(Aminosulfonyl)amino]ethyl}amino)-N-[(4-bromo-2-furyl)methyl]-N'-hydroxy-1 , 2,5- Diazole-3-carboxamide

在微波小瓶中，將3-{4-[(2-胺基乙基)胺基]-1,2,5-二唑-3-基}-4-[(4-溴-2-呋喃基)甲基]-1,2,4-二唑-5(4H )-酮氫碘酸鹽(30 mg，0.060 mmol)及磺醯胺(29 mg，0.30 mmol)懸浮於吡啶(1 mL)中。以氮氣沖洗反應混合物且在微波反應器中、在130℃下加熱3分鐘。移除溶劑且將粗中間物懸浮於甲醇(1 mL)中。以一份添加NaOH於水中之2.0 N溶液(0.30 mL，0.60 mmol)且將反應物加熱至45℃歷時30分鐘。以乙酸(68 μL，1.2 mmol)中和後，藉由製備型LCMS純化產物產生所要產物(10.4 mg，41%)。C10 H15 BrN7 O5 S(M+H)+ 之LCMS計算值：m/z=423.9,426.0。1 H NMR(400 MHz,DMSO-d 6 )：δ10.87(s,1 H),7.75(s,1 H),6.83(t,J =7.3 Hz,1 H),6.68(t,J =6.0 Hz,1 H),6.56(s,2 H),6.30(t,J =6.0 Hz,1 H),6.23(s,1 H),4.56(d,J =7.0 Hz,2 H),3.32(q,J =6.3 Hz,2 H),3.07(q,J =6.3 Hz,2 H)。In a microwave vial, 3-{4-[(2-aminoethyl)amino]-1,2,5- Diazol-3-yl}-4-[(4-bromo-2-furyl)methyl]-1,2,4- The oxazol-5( 4H )-one hydroiodide (30 mg, 0.060 mmol) and sulfonamide (29 mg, 0.30 mmol) were suspended in pyridine (1 mL). The reaction mixture was flushed with nitrogen and heated in a microwave reactor at 130 ° C for 3 min. The solvent was removed and the crude intermediate was suspended in methanol (1 mL). A 2.0 N solution (0.30 mL, 0.60 mmol) with NaOH in water was added and the mixture was warmed to 45 ° C for 30 min. After neutralization with acetic acid (68 μL, 1.2 mmol), product was purified by preparative LCMS to give the desired product (10.4 mg, 41%). C 10 H 15 BrN 7 O 5 S (M + H) + The LCMS calc: m / z = 423.9,426.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 10.87 (s, 1 H), 7.75 (s, 1 H), 6.83 (t, J = 7.3 Hz, 1 H), 6.68 (t, J = 6.0 Hz, 1 H), 6.56 (s, 2 H), 6.30 (t, J = 6.0 Hz, 1 H), 6.23 (s, 1 H), 4.56 (d, J = 7.0 Hz, 2 H), 3.32 (q, J = 6.3 Hz, 2 H), 3.07 (q, J = 6.3 Hz, 2 H).

實例21Example 21 4-({2-[(胺基磺醯基)胺基]乙基}胺基)- N -[(4-氯-2-呋喃基)甲基]- N' -羥基-1,2,5- 二唑-3-甲醯亞胺醯胺 4 - ({2 - [(sulfo amino acyl) amino] ethyl} amino) - N - [(4- chloro-2-furyl) methyl] - N '- hydroxy-1,2, 5- Diazole-3-carboxamide

步驟A：4-氯-2-糠醛Step A: 4-Chloro-2-furaldehyde

在氮氣氛圍下經15分鐘向三氯化鋁(29.8 g，0.223 mol)於二氯甲烷(200 mL)中之經攪拌懸浮液中添加2-呋喃甲醛(8.44 mL，0.102 mol)。攪拌30分鐘後，使用吸移管、使氯氣在懸浮液中鼓泡50分鐘。將燒瓶密封且在室溫下攪拌90小時。將反應混合物緩慢添加至冰(500 mL)於1.0 N氯化氫水溶液(300 mL)中的混合物中。經隨後1小時將混合物溫至室溫。分離各層且收集有機層。以二氯甲烷(2×200 mL)萃取其他產物。以水(250 mL)洗滌經合併之有機層且經硫酸鈉乾燥。真空移除溶劑產生含有所要產物之粗混合物(14.0 g，100%，60%純度)。1 H NMR(400 MHz,DMSO-d 6 )：δ9.56(s,1 H),8.36(s,1 H),7.71(s,1 H)。To a stirred suspension of aluminum trichloride (29.8 g, 0.223 mol) in dichloromethane (200 mL) was added 2-furfuraldehyde (8.44 mL, 0.102 mol) over 15 min. After stirring for 30 minutes, chlorine gas was bubbled through the suspension for 50 minutes using a pipette. The flask was sealed and stirred at room temperature for 90 hours. The reaction mixture was slowly added to a mixture of ice (500 mL) &lt The mixture was warmed to room temperature over the next 1 hour. The layers were separated and the organic layer was collected. The other product was extracted with dichloromethane (2 x 200 mL). The combined organic layers were washed with water (250 mL) and dried over sodium sulfate. Removal of the solvent in vacuo gave a crude mixture (14.0 g, 100%, 60% purity) containing the desired product. 1 H NMR (400 MHz, DMSO- d 6): δ9.56 (s, 1 H), 8.36 (s, 1 H), 7.71 (s, 1 H).

步驟B：[(4-氯-2-呋喃基)甲基]胺基甲酸第三丁酯Step B: [(4-Chloro-2-furyl)methyl]aminocarboxylic acid tert-butyl ester

將4-氯-2-糠醛(14.0 g，60%純度，64 mmol)溶解於乙醇(50 mL)及水(50 mL)中。依序添加N -羥基胺鹽酸鹽(12.6 g，182 mmol)及乙酸鈉(14.9 g，182 mmol)且使反應混合物在100℃下回流1小時。將溶液部分濃縮，接著添加水(25 mL)及乙酸乙酯(50 mL)。收集有機層且以乙酸乙酯(2×25 mL)萃取水層。以鹽水(50 mL)及水(50 mL)洗滌經合併之有機層。經硫酸鈉乾燥後，真空濃縮溶液。將中間物懸浮於乙酸(115 mL)中。將溶液在冰浴中冷卻且經20分鐘逐份添加鋅(33.1 g，506 mmol)。將反應物經2小時溫至室溫且經由矽藻土過濾。真空移除溶劑。4-Chloro-2-furaldehyde (14.0 g, 60% purity, 64 mmol) was dissolved in ethanol (50 mL) and water (50 mL). N -Hydroxylamine hydrochloride (12.6 g, 182 mmol) and sodium acetate (14.9 g, 182 mmol) were sequentially added and the mixture was refluxed at 100 ° C for one hour. The solution was partially concentrated, followed by water (25 mL) and ethyl acetate (50 mL). The organic layer was collected and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with brine (50 mL) and water (50 mL). After drying over sodium sulfate, the solution was concentrated in vacuo. The intermediate was suspended in acetic acid (115 mL). The solution was cooled in an ice bath and zinc (33.1 g, 506 mmol) was added portionwise over 20 min. The reaction was warmed to room temperature over 2 h and filtered over Celite. The solvent was removed in vacuo.

將殘餘物在四氫呋喃(100 mL)中攪拌。經30分鐘逐滴添加2.0 M NaOH於水中之溶液(152 mL，304 mmol)。將反應混合物置於冰浴中且在5分鐘後，經15分鐘逐滴添加二碳酸二-第三丁酯(24.3 g，111 mmol)。經隨後2小時將反應物溫至室溫且接著真空移除四氫呋喃。添加乙酸乙酯(100 mL)且過濾懸浮液。收集有機層且以乙酸乙酯(2×100 mL)萃取水層。以水/鹽水之1：1混合物(100 mL)洗滌經合併之有機層，經硫酸鈉乾燥且真空濃縮。藉由矽膠急驟層析法(使用己烷中之乙酸乙酯作為溶離劑)純化產生所要產物(3.05 g，22%)。C10 H14 ClNNaO3 (M+Na)+ 之LCMS計算值：m/z=253.9。1 H NMR(400 MHz,DMSO-d 6 )：δ7.81(s,1 H),7.37(t,J =5.3 Hz,1 H),6.32(s,1 H),4.05(d,J =6.0 Hz,2 H),1.36(s,9 H)。The residue was stirred in tetrahydrofuran (100 mL). A solution of 2.0 M NaOH in water (152 mL, 304 mmol) was added dropwise over 30 min. The reaction mixture was placed in an ice bath and after 5 min, di-t-butyl dicarbonate (24.3 g, 111 mmol) was added dropwise over 15 min. The reaction was warmed to room temperature over 2 hours and then the tetrahydrofuran was removed in vacuo. Ethyl acetate (100 mL) was added and the suspension was filtered. The organic layer was collected and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with EtOAc EtOAc m. Purification by silica gel flash chromatography (using ethyl acetate in hexanes as solvent) gave the desired product (3.05 g, 22%). C 10 H 14 ClNNaO 3 (M + Na) + The LCMS calc: m / z = 253.9. 1 H NMR (400 MHz, DMSO- d 6 ): δ 7.81 (s, 1 H), 7.37 (t, J = 5.3 Hz, 1 H), 6.32 (s, 1 H), 4.05 (d, J = 6.0 Hz, 2 H), 1.36 (s, 9 H).

步驟C：1-(4-氯-2-呋喃基)甲胺三氟乙酸鹽Step C: 1-(4-Chloro-2-furanyl)methylamine trifluoroacetate

使用[(4-氯-2-呋喃基)甲基]胺基甲酸第三丁酯作為起始物質、根據實例20步驟B 之程序製備所要化合物(定量產量)。C5 H4 ClO(M-NH2 )+ 之LCMS計算值：m/z=115.0。1 H NMR(400 MHz,DMSO-d 6 )：δ8.29(br s,3 H),8.04(s,1 H),6.69(s,1 H),4.07(s,2 H)。The desired compound (quantitative yield) was prepared according to the procedure of Example 20, Step B , using &lt;RTI ID=0.0&gt;&gt; C 5 H 4 ClO (M- NH 2) + sum LCMS calc: m / z = 115.0. 1 H NMR (400 MHz, DMSO- d 6): δ8.29 (br s, 3 H), 8.04 (s, 1 H), 6.69 (s, 1 H), 4.07 (s, 2 H).

步驟D：N-[(4-氯-2-呋喃基)甲基]-N'-羥基-4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯胺Step D: N-[(4-Chloro-2-furyl)methyl]-N'-hydroxy-4-[(2-methoxyethyl)amino]-1,2,5- Diazole-3-carboxamide

使用N -羥基-4-(2-甲氧基乙基胺基)-1,2,5-二唑-3-伸亞胺醯氯及1-(4-氯-2-呋喃基)甲胺三氟乙酸鹽作為起始物質、根據實例20步驟C 之程序製備所要化合物(定量產量)。C11 H15 ClN5 O4 (M+H)+ 之LCMS計算值：m/z=316.0。Using N -hydroxy-4-(2-methoxyethylamino)-1,2,5- The desired compound (quantitative yield) was prepared according to the procedure of Example 20, Step C , using oxazol-3-ylidene chloride and 1-(4-chloro-2-furanyl)methylamine trifluoroacetate as starting material. C 11 H 15 ClN 5 O 4 (M + H) + The LCMS calc: m / z = 316.0.

步驟E：4-[(4-氯-2-呋喃基)甲基]-3-{4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H)-酮Step E: 4-[(4-Chloro-2-furyl)methyl]-3-{4-[(2-methoxyethyl)amino]-1,2,5- Diazol-3-yl}-1,2,4- Diazol-5(4H)-one

使用N -[(4-氯-2-呋喃基)甲基]-N' -羥基-4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯胺作為起始物質、根據實例20步驟D 之程序製備所要化合物(51%產率)。C12 H13 ClN5 O5 (M+H)+ 之LCMS計算值：m/z=342.0。Using N -[(4-chloro-2-furyl)methyl] -N' -hydroxy-4-[(2-methoxyethyl)amino]-1,2,5- The desired compound (51% yield) was prepared according to the procedure of Example 20 Step D. C 12 H 13 ClN 5 O 5 (M + H) + The LCMS calc: m / z = 342.0.

步驟F：4-[(4-氯-2-呋喃基)甲基]-3-{4-[(2-羥基乙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H)-酮Step F: 4-[(4-Chloro-2-furyl)methyl]-3-{4-[(2-hydroxyethyl)amino]-1,2,5- Diazol-3-yl}-1,2,4- Diazol-5(4H)-one

使用4-[(4-氯-2-呋喃基)甲基]-3-{4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H )-酮作為起始物質、根據實例20步驟E 之程序製備所要化合物(定量產量)。C11 H10 ClN5 NaO5 (M+Na)+ 之LCMS計算值：m/Z=349.9。4-[(4-Chloro-2-furyl)methyl]-3-{4-[(2-methoxyethyl)amino]-1,2,5- Diazol-3-yl}-1,2,4- The desired compound (quantitative yield) was prepared according to the procedure of Example 20, Step E , using oxazol-5( 4H )-one as starting material. C 11 H 10 ClN 5 NaO 5 (M + Na) + The LCMS calc: m / Z = 349.9.

步驟G：甲烷磺酸2-[(4-{4-[(4-氯-2-呋喃基)甲基]-5-側氧基-4,5-二氫-1,2,4-二唑-3-基}-1,2,5-二唑-3-基)胺基]乙酯Step G: methanesulfonic acid 2-[(4-{4-[(4-chloro-2-furyl)methyl]-5- pendantoxy-4,5-dihydro-1,2,4- Diazol-3-yl}-1,2,5- Diazol-3-yl)amino]ethyl ester

使用4-[(4-氯-2-呋喃基)甲基]-3-{4-[(2-羥基乙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H )-酮作為起始物質、根據實例20步驟F 之程序製備所要化合物(69%產率)。C12 H13 ClN5 O7 S(M+H)+ 之LCMS計算值：m/z=405.8。4-[(4-Chloro-2-furyl)methyl]-3-{4-[(2-hydroxyethyl)amino]-1,2,5- Diazol-3-yl}-1,2,4- Oxadiazol -5 (4 H) - one as a starting material, the desired compound (69% yield) was prepared according to the procedure of Example 20 Step F. C 12 H 13 ClN 5 O 7 S (M + H) + The LCMS calc: m / z = 405.8.

步驟H：3-{4-[(2-疊氮基乙基)胺基]-1,2,5-二唑-3-基}-4-[(4-氯-2-呋喃基)甲基]-1,2,4-二唑-5(4H)-酮Step H: 3-{4-[(2-azidoethyl)amino]-1,2,5- Diazol-3-yl}-4-[(4-chloro-2-furyl)methyl]-1,2,4- Diazol-5(4H)-one

使用甲烷磺酸2-[(4-{4-[(4-氯-2-呋喃基)甲基]-5-側氧基-4,5-二氫-1,2,4-二唑-3-基}-1,2,5-二唑-3-基)胺基]乙酯作為起始物質、根據實例20步驟G 之程序製備所要化合物(定量產量)。C11 H9 ClN8 NaO4 (M+Na)+ 之LCMS計算值：m/z=374.9。2-[(4-{4-[(4-Chloro-2-furyl)methyl]-5-sideoxy-4,5-dihydro-1,2,4- methanesulfonate Diazol-3-yl}-1,2,5- The oxazol-3-yl)amino]ethyl ester was used as the starting material to give the desired compound (quantitative yield) according to the procedure of Example 20 Step G. C 11 H 9 ClN (M + Na) + The LCMS calc 8 NaO 4: m / z = 374.9.

步驟I：3-{4-[(2-胺基乙基)胺基]-1,2,5-二唑-3-基}-4-[(4-氯-2-呋喃基)甲基]-1,2,4-二唑-5(4H)-酮氫碘酸鹽Step I: 3-{4-[(2-Aminoethyl)amino]-1,2,5- Diazol-3-yl}-4-[(4-chloro-2-furyl)methyl]-1,2,4- Diazol-5(4H)-one hydroiodide

使用3-{4-[(2-疊氮基乙基)胺基]-1,2,5-二唑-3-基}-4-[(4-氯-2-呋喃基)甲基]-1,2,4-二唑-5(4H )-酮作為起始物質、根據實例20步驟H 製備所要化合物(57%產率)。C11 H12 ClN6 O4 (M+H)+ 之LCMS計算值：m/z=326.9。Using 3-{4-[(2-azidoethyl)amino]-1,2,5- Diazol-3-yl}-4-[(4-chloro-2-furyl)methyl]-1,2,4- Oxadiazol -5 (4 H) - one as a starting material, in accordance with the procedure of Example 20 the desired compound H was prepared (57% yield). C 11 H 12 ClN 6 O 4 (M + H) + The LCMS calc: m / z = 326.9.

步驟J：4-({2-[(胺基磺醯基)胺基]乙基}胺基)-N-[(4-氯-2-呋喃基)甲基]-N'-羥基-1,2,5-二唑-3-甲醯亞胺醯胺Step J: 4-({2-[(Aminosulfonyl)amino]ethyl}amino)-N-[(4-chloro-2-furyl)methyl]-N'-hydroxy-1 , 2,5- Diazole-3-carboxamide

使用3-{4-[(2-胺基乙基)胺基]-1,2,5-二唑-3-基}-4-[(4-氯-2-呋喃基)甲基]-1,2,4-二唑-5(4H )-酮氫碘酸鹽作為起始物質、根據實例20步驟I 製備所要化合物(53%產率)。C10 H15 ClN7 O5 S(M+H)+ 之LCMS計算值：m/z=379.9。1 H NMR(400 MHz,DMSO-d 6 )：δ10.88(s,1 H),7.77(s,1 H),6.83(t,J =6.8 Hz,1 H),6.68(t,J =5.9 Hz,1 H),6.56(s,2 H),6.30(t,J =5.9 Hz,1 H),6.22(s,1 H),4.55(d,2 H),3.32(q,J =6.3 Hz,2 H),3.06(q,J =6.3 Hz,2 H)。Using 3-{4-[(2-aminoethyl)amino]-1,2,5- Diazol-3-yl}-4-[(4-chloro-2-furyl)methyl]-1,2,4- Oxadiazol -5 (4 H) - -one hydroiodide as the starting material, according to the procedure of Example I 20 Preparation of desired compound (53% yield). C 10 H 15 ClN 7 O 5 S (M + H) + The LCMS calc: m / z = 379.9. 1 H NMR (400 MHz, DMSO- d 6 ): δ 10.88 (s, 1 H), 7.77 (s, 1 H), 6.83 (t, J = 6.8 Hz, 1 H), 6.68 (t, J = 5.9 Hz, 1 H), 6.56 (s, 2 H), 6.30 (t, J = 5.9 Hz, 1 H), 6.22 (s, 1 H), 4.55 (d, 2 H), 3.32 (q, J = 6.3 Hz, 2 H), 3.06 (q, J = 6.3 Hz, 2 H).

實例22Example 22 中間物3-(4-(2-胺基乙基胺基)-1,2,5- 二唑-3-基)-4-(3-溴-4-氟苯基)-1,2,4- 二唑-5(4H)-酮氫碘酸鹽之替代製備 Intermediate 3-(4-(2-Aminoethylamino)-1,2,5- Diazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4- Alternative preparation of oxazol-5(4H)-one hydroiodide

步驟A：4-胺基-N' -羥基-N -(2-甲氧基乙基)-1,2,5-二唑-3-甲醯亞胺醯胺Step A: 4-Amino- N' -hydroxy- N- (2-methoxyethyl)-1,2,5- Diazole-3-carboxamide

將4-胺基-N -羥基-1,2,5-二唑-3-甲醯亞胺醯氯(可根據實例1步驟A-B 製備，200.0 g，1.23 mol)與乙酸乙酯(1.2 L)混合。在0-5℃下，在攪拌下以一份添加2-甲氧基乙胺[Aldrich,產品號143693](119.0 mL，1.35 mol)。反應溫度升至41℃。將反應物冷卻至0-5℃。添加三乙胺(258 mL，1.84 mol)。攪拌5分鐘後，LCMS指示反應完成。以水(500 mL)及鹽水(500 mL)洗滌反應溶液，經硫酸鈉乾燥，且濃縮產生呈暗黑色粗油狀之所要產物(294 g，119%)。C6 H12 N5 O3 (M+H)+ 之LCMS：m/z=202.3。1 H NMR(400 MHz,DMSO-d 6 )：δ10.65(s,1 H),6.27(s,2 H),6.10(t,J =6.5 Hz,1 H),3.50(m,2 H),3.35(d,J =5.8 Hz,2 H),3.08(s,3 H)。4-Amino- N -hydroxy-1,2,5- The oxazol-3-carboximine oxime chloride (prepared according to Example 1 Step AB , 200.0 g, 1.23 mol) was combined with ethyl acetate (1.2 L). 2-Methoxyethylamine [Aldrich, product number 143693] (119.0 mL, 1.35 mol) was added in one portion with stirring at 0-5 °C. The reaction temperature rose to 41 °C. The reaction was cooled to 0-5 °C. Triethylamine (258 mL, 1.84 mol) was added. After stirring for 5 minutes, LCMS indicated the reaction was completed. The reaction solution was washed with EtOAc (EtOAc m. C 6 H 12 N 5 O 3 (M + H) + The LCMS: m / z = 202.3. 1 H NMR (400 MHz, DMSO- d 6 ): δ 10.65 (s, 1 H), 6.27 (s, 2 H), 6.10 (t, J = 6.5 Hz, 1 H), 3.50 (m, 2 H) ), 3.35 (d, J = 5.8 Hz, 2 H), 3.08 (s, 3 H).

步驟B：N' -羥基-4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯胺Step B: N' -hydroxy-4-[(2-methoxyethyl)amino]-1,2,5- Diazole-3-carboxamide

使4-胺基-N' -羥基-N -(2-甲氧基乙基)-1,2,5-二唑-3-甲醯亞胺醯胺(248.0 g，1.23 mol)與水(1 L)混合。添加氫氧化鉀(210 g，3.7 mol)。使反應物在100℃下回流隔夜(15小時)。使用己烷中之50%乙酸乙酯(含有1%氫氧化銨)之TLC指示反應完成(產物Rf=0.6，起始物質Rf=0.5)。LCMS亦指示反應完成。將反應物冷卻至室溫且以乙酸乙酯(3×1 L)萃取。經硫酸鈉乾燥經合併之乙酸乙酯溶液且濃縮產生呈灰白色粗固體狀之所要產物(201 g，81%)。C6 H12 N5 O3 (M+H)+ 之LCMS：m/z=202.3。1 H NMR(400 MHz,DMSO-d 6 )：δ10.54(s,1 H),6.22(s,2 H),6.15(t,J =5.8 Hz,1 H),3.45(t,J =5.3 Hz,2 H),3.35(m,2 H),3.22(s,3 H)。4-Amino- N' -hydroxy- N- (2-methoxyethyl)-1,2,5- The oxazol-3-carboxamimidamide (248.0 g, 1.23 mol) was mixed with water (1 L). Potassium hydroxide (210 g, 3.7 mol) was added. The reaction was refluxed overnight (15 hours) at 100 °C. TLC using 50% ethyl acetate in hexanes (1% ammonium hydroxide) indicated the reaction was completed (product Rf = 0.6, starting material Rf = 0.5). LCMS also indicated that the reaction was complete. The reaction was cooled to room temperature and extracted with ethyl acetate (3×1 L). The combined ethyl acetate solution was dried <RTI ID=0.0> C 6 H 12 N 5 O 3 (M + H) + The LCMS: m / z = 202.3. 1 H NMR (400 MHz, DMSO- d 6 ): δ 10.54 (s, 1 H), 6.22 (s, 2 H), 6.15 (t, J = 5.8 Hz, 1 H), 3.45 (t, J = 5.3 Hz, 2 H), 3.35 (m, 2 H), 3.22 (s, 3 H).

步驟C：N -羥基-4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯氯Step C: N -Hydroxy-4-[(2-methoxyethyl)amino]-1,2,5- Diazole-3-carboximine

在室溫下，將N' -羥基-4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯胺(50.0 g，0.226 mol)溶解於6.0 M鹽酸水溶液(250 mL，1.5 mol)中。添加氯化鈉(39.5 g，0.676 mol)，隨後添加水(250 mL)及乙酸乙酯(250 mL)。在3-5℃下，經1小時緩慢添加預先製備之亞硝酸鈉(15.0 g，0.217 mol)水溶液(100 mL)。將反應物在3-8℃下攪拌2小時，且接著在室溫下攪拌整個週末。LCMS指示反應完成。以乙酸乙酯(2×200 mL)萃取反應溶液。經硫酸鈉乾燥經合併之乙酸乙酯溶液且濃縮產生呈白色粗固體狀之所要產物(49.9 g，126%)。C6 H10 ClN4 O3 (M+H)+ 之LCMS：m/z=221.0。1 H NMR(400 MHz,DMSO-d 6 )：δ13.43(s,1 H),5.85(t,J =5.6 Hz,1 H),3.50(t,J =5.6 Hz,2H),3.37(dd,J =10.8,5.6 Hz,2 H),3.25(s,3 H)。 N' -hydroxy-4-[(2-methoxyethyl)amino]-1,2,5- at room temperature The oxazol-3-carboxamimidamide (50.0 g, 0.226 mol) was dissolved in 6.0 M aqueous hydrochloric acid (250 mL, 1.5 mol). Sodium chloride (39.5 g, 0.676 mol) was added followed by water (250 mL) and ethyl acetate (250 mL). A pre-prepared aqueous solution of sodium nitrite (15.0 g, 0.217 mol) (100 mL) was slowly added over 1 hour at 3-5 °C. The reaction was stirred at 3-8 °C for 2 hours and then stirred at room temperature over the weekend. LCMS indicated the reaction was complete. The reaction solution was extracted with ethyl acetate (2×200 mL). The combined ethyl acetate solution was dried <RTI ID=0.0> C 6 H 10 ClN 4 O 3 (M + H) + The LCMS: m / z = 221.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 13.43 (s, 1 H), 5.85 (t, J = 5.6 Hz, 1 H), 3.50 (t, J = 5.6 Hz, 2H), 3.37 ( Dd, J = 10.8, 5.6 Hz, 2 H), 3.25 (s, 3 H).

步驟D：N -(3-溴-4-氟苯基)-N' -羥基-4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯胺Step D: N - (3- bromo-4-fluorophenyl) - N '- hydroxy-4 - [(2-methoxyethyl) amino] -1,2,5 Diazole-3-carboxamide

使N -羥基-4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯氯(46.0 g，0.208 mol)與水(300 mL)混合。將混合物加熱至60℃。添加3-溴-4-氟苯胺[Oakwood products，產品號013091](43.6 g，0.229 mol)且攪拌10分鐘。經15分鐘添加溫碳酸氫鈉(26.3 g，0.313 mol)溶液(300 mL水)。將反應物在60℃下攪拌20分鐘。LCMS指示反應完成。將反應溶液冷卻至室溫且以乙酸乙酯(2×300 mL)萃取。經硫酸鈉乾燥經合併之乙酸乙酯溶液且濃縮產生呈棕色粗固體狀之所要產物(76.7 g，98%)。C12 H14 BrFN5 O3 (M+H)+ 之LCMS：m/z=374.0,376.0。1 H NMR(400 MHz,DMSO-d 6 )：δ11.55(s,1 H),8.85(s,1 H),7.16(t,J =8.8 Hz,1 H),7.08(dd,J =6.1,2.7 Hz,1 H),6.75(m,1 H),6.14(t,J =5.8 Hz,1 H),3.48(t,J =5.2 Hz,2 H),3.35(dd,J =10.8,5.6 Hz,2 H),3.22(s,3 H)。 N -hydroxy-4-[(2-methoxyethyl)amino]-1,2,5- The oxazol-3-carboximine oxime chloride (46.0 g, 0.208 mol) was mixed with water (300 mL). The mixture was heated to 60 °C. 3-Bromo-4-fluoroaniline [Oakwood products, product number 013091] (43.6 g, 0.229 mol) was added and stirred for 10 minutes. A solution of warm sodium bicarbonate (26.3 g, 0.313 mol) (300 mL water) was added over 15 minutes. The reaction was stirred at 60 ° C for 20 minutes. LCMS indicated the reaction was complete. The reaction solution was cooled to room temperature and extracted with ethyl acetate (2×300 mL). The combined ethyl acetate solution was dried <RTI ID=0.0> C 12 H 14 BrFN 5 O 3 (M + H) + The LCMS: m / z = 374.0,376.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 11.55 (s, 1 H), 8.85 (s, 1 H), 7.16 (t, J = 8.8 Hz, 1 H), 7.08 (dd, J = 6.1, 2.7 Hz, 1 H), 6.75 (m, 1 H), 6.14 (t, J = 5.8 Hz, 1 H), 3.48 (t, J = 5.2 Hz, 2 H), 3.35 (dd, J = 10.8) , 5.6 Hz, 2 H), 3.22 (s, 3 H).

步驟E：4-(3-溴-4-氟苯基)-3-{4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H )-酮Step E: 4-(3-Bromo-4-fluorophenyl)-3-{4-[(2-methoxyethyl)amino]-1,2,5- Diazol-3-yl}-1,2,4- Diazol-5(4 H )-one

將N -(3-溴-4-氟苯基)-N' -羥基-4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-甲醯亞胺醯胺(76.5 g，0.204 mol)、1,1'-羰基二咪唑(49.7 g，0.307 mol)與乙酸乙酯(720 mL)之混合物加熱至60℃且攪拌20分鐘。LCMS指示反應完成。將反應物冷卻至室溫，以1 N HCl(2×750 mL)洗滌，經硫酸鈉乾燥，且濃縮產生呈棕色粗固體狀之所要產物(80.4 g，98%)。C13 H12 BrFN5 O4 (M+H)+ 之LCMS：m/z=400.0,402.0。1 H NMR(400 MHz,DMSO-d 6 )：67.94(t,J =8.2 Hz,1 H),7.72(dd,J =9.1,2.3 Hz,1 H),7.42(m,1 H),6.42(t,J =5.7 Hz,1 H),3.46(t,J =5.4 Hz,2 H),3.36(t,J =5.8 Hz,2 H),3.26(s,3 H)。The N - (3- bromo-4-fluorophenyl) - N '- hydroxy-4 - [(2-methoxyethyl) amino] -1,2,5 A mixture of oxazol-3-carboxamimidamide (76.5 g, 0.204 mol), 1,1'-carbonyldiimidazole (49.7 g, 0.307 mol) and ethyl acetate (720 mL) was heated to 60 ° C and stirred. 20 minutes. LCMS indicated the reaction was complete. The reaction was cooled to rt EtOAc (EtOAc)EtOAc. C 13 H 12 BrFN 5 O 4 (M + H) + The LCMS: m / z = 400.0,402.0. 1 H NMR (400 MHz, DMSO- d 6 ): 67.94 (t, J = 8.2 Hz, 1 H), 7.72 (dd, J = 9.1, 2.3 Hz, 1 H), 7.42 (m, 1 H), 6.42 (t, J = 5.7 Hz, 1 H), 3.46 (t, J = 5.4 Hz, 2 H), 3.36 (t, J = 5.8 Hz, 2 H), 3.26 (s, 3 H).

步驟F：4-(3-溴-4-氟苯基)-3-{4-[(2-羥基乙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H )-酮Step F: 4-(3-Bromo-4-fluorophenyl)-3-{4-[(2-hydroxyethyl)amino]-1,2,5- Diazol-3-yl}-1,2,4- Diazol-5(4 H )-one

將4-(3-溴-4-氟苯基)-3-{4-[(2-甲氧基乙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H )-酮(78.4 g，0.196 mol)溶解於二氯甲烷(600 mL)中。在-67℃下，經15分鐘添加三溴化硼(37 mL，0.392 mol)。將反應物在30分鐘內溫至-10℃。LCMS指示反應完成。將反應物在室溫下攪拌1小時。在0-5℃下，以碳酸氫鈉飽和溶液(1.5 L)經30分鐘緩慢中止反應。反應溫度升至25℃。以乙酸乙酯(2×500 mL，第一萃取有機層立於底部且第二萃取有機層位於頂部)萃取反應物。經硫酸鈉乾燥經合併之有機層且濃縮產生呈棕色粗固體狀之所要產物(75 g，99%)。C12 H10 BrFN5 O4 (M+H)+ 之LCMS：m/z=386.0,388.0。1 H NMR(400 MHz,DMSO-d 6 )：δ8.08(dd,J =6.2,2.5 Hz,1 H),7.70(m,1 H),7.68(t,J =8.7 Hz,1 H),6.33(t,J =5.6 Hz,1 H),4.85(t,J =5.0 Hz,1 H),3.56(dd,J =10.6,5.6 Hz,2 H),3.29(dd,J =11.5,5.9 Hz,2 H)。4-(3-Bromo-4-fluorophenyl)-3-{4-[(2-methoxyethyl)amino]-1,2,5- Diazol-3-yl}-1,2,4- The oxazol-5( 4H )-one (78.4 g, 0.196 mol) was dissolved in dichloromethane (600 mL). Boron tribromide (37 mL, 0.392 mol) was added over 15 minutes at -67 °C. The reaction was warmed to -10 °C over 30 minutes. LCMS indicated the reaction was complete. The reaction was stirred at room temperature for 1 hour. The reaction was slowly quenched with a saturated solution of sodium bicarbonate (1.5 L) at 0-5 ° C over 30 min. The reaction temperature was raised to 25 °C. The reaction was extracted with ethyl acetate (2 x 500 mL, the first extracted organic layer stood at the bottom and the second extracted organic layer was at the top). The combined organic layers were dried <RTI ID=0.0> C 12 H 10 BrFN 5 O 4 (M + H) + The LCMS: m / z = 386.0,388.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.08 (dd, J = 6.2, 2.5 Hz, 1 H), 7.70 (m, 1 H), 7.68 (t, J = 8.7 Hz, 1 H) , 6.33 (t, J = 5.6 Hz, 1 H), 4.85 (t, J = 5.0 Hz, 1 H), 3.56 (dd, J = 10.6, 5.6 Hz, 2 H), 3.29 (dd, J =11.5, 5.9 Hz, 2 H).

步驟G：甲烷磺酸2-({4-[4-(3-溴-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}胺基)乙酯Step G: 2-({4-[4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4- methanesulfonic acid) Diazol-3-yl]-1,2,5- Diazol-3-yl}amino)ethyl ester

將4-(3-溴-4-氟苯基)-3-(4-(2-羥基乙基胺基)-1,2,5-二唑-3-基)-1,2,4-二唑-5(4H)-酮(72.2 g，0.188 mol)與乙酸乙酯(600 mL)混合。添加甲烷磺醯氯(19.2 mL，0.248 mol)，隨後添加三乙胺(34.9 mL，0.250 mol)。將反應物在室溫下攪拌5分鐘。當LCMS指示反應完成時(M+H=442)，向反應物中添加500 mL水。以乙酸乙酯(2×500 mL)萃取反應物。以鹽水(500 mL)洗滌經合併之乙酸乙酯溶液，經硫酸鈉乾燥且濃縮產生85.1 g棕色粗固體。1 H NMR核實結構。粗產率為97%。C13 H11 BrFN5 O6 SNa(M+Na)+ 之LCMS：m/z=485.9,487.9。1 H NMR(400 MHz,DMSO-d 6 )：δ8.08(dd,J =6.2,2.5 Hz,1 H),7.72(m,1 H),7.58(t,J =8.7 Hz,1 H),6.75(t,J =5.9 Hz,1 H),4.36(t,J =5.3 Hz,2 H),3.58(dd,J =11.2,5.6 Hz,2 H),3.18(s,3 H)。4-(3-Bromo-4-fluorophenyl)-3-(4-(2-hydroxyethylamino)-1,2,5- Diazol-3-yl)-1,2,4- The oxazol-5(4H)-one (72.2 g, 0.188 mol) was combined with ethyl acetate (600 mL). Methane sulfonium chloride (19.2 mL, 0.248 mol) was added followed by triethylamine (34.9 mL, 0.250 mol). The reaction was stirred at room temperature for 5 minutes. When LCMS indicated the completion of the reaction (M+H = 442), 500 mL of water was added to the mixture. The reaction was extracted with ethyl acetate (2×500 mL). The combined ethyl acetate solution was washed with brine (500 mL) dried over sodium sulfate. The structure was verified by 1 H NMR. The crude yield was 97%. C 13 H 11 BrFN 5 O 6 SNa (M + Na) + The LCMS: m / z = 485.9,487.9. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.08 (dd, J = 6.2, 2.5 Hz, 1 H), 7.72 (m, 1 H), 7.58 (t, J = 8.7 Hz, 1 H) , 6.75 (t, J = 5.9 Hz, 1 H), 4.36 (t, J = 5.3 Hz, 2 H), 3.58 (dd, J = 11.2, 5.6 Hz, 2 H), 3.18 (s, 3 H).

步驟H：3-{4-[(2-疊氮基乙基)胺基]-1,2,5-二唑-3-基}-4-(3-溴-4-氟苯基)-1,2,4-二唑-5(4H )-酮Step H: 3-{4-[(2-azidoethyl)amino]-1,2,5- Diazol-3-yl}-4-(3-bromo-4-fluorophenyl)-1,2,4- Diazol-5(4 H )-one

將甲烷磺酸2-(4-(4-(3-溴-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基)-1,2,5-二唑-3-基胺基)乙酯(50.0 g，0.108 mol)溶解於N,N -二甲基甲醯胺(83 mL)中。添加疊氮化鈉(10.5 g，0.162 mol)。將反應物在65℃下攪拌5-6小時。LCMS指示反應完成(M+Na=435)。以水(250 mL)中止反應物且以乙酸乙酯(2×25 mL)萃取。以水(250 mL，層分離緩慢進行，添加100 mL鹽水以改良分離)洗滌經合併之乙酸乙酯溶液，經硫酸鈉乾燥，且濃縮產生49.7 g棕色粗固體。粗固體產率為112%。C12 H8 BrFN8 O3 Na(M+Na)+ 之LCMS：m/z=433.0,435.0。1 H NMR(400 MHz,DMSO-d 6 )：δ8.08(dd,J =6.2,2.5 Hz,1 H),7.72(m,1 H),7.58(t,J =8.7 Hz,1 H),6.75(t,J =5.7 Hz,1 H),3.54(t,J =5.3 Hz,2 H),3.45(dd,J =11.1,5.2 Hz,2 H)。2-(4-(4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4- methanesulfonate Diazol-3-yl)-1,2,5- The oxazol-3-ylamino)ethyl ester (50.0 g, 0.108 mol) was dissolved in N,N -dimethylformamide (83 mL). Sodium azide (10.5 g, 0.162 mol) was added. The reaction was stirred at 65 ° C for 5-6 hours. LCMS indicated the completion of the reaction (M+Na = 435). The reaction was quenched with water (250 mL)EtOAcEtOAc The combined ethyl acetate solution was washed with water (250 mL, EtOAc (EtOAc)EtOAc. The crude solid yield was 112%. C 12 H 8 BrFN 8 O 3 Na (M + Na) + The LCMS: m / z = 433.0,435.0. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.08 (dd, J = 6.2, 2.5 Hz, 1 H), 7.72 (m, 1 H), 7.58 (t, J = 8.7 Hz, 1 H) , 6.75 (t, J = 5.7 Hz, 1 H), 3.54 (t, J = 5.3 Hz, 2 H), 3.45 (dd, J = 11.1, 5.2 Hz, 2 H).

步驟I：3-(4-(2-胺基乙基胺基)-1,2,5-二唑-3-基)-4-(3-溴-4-氟苯基)-1,2,4-二唑-5(4H)-酮氫碘酸鹽Step I: 3-(4-(2-Aminoethylamino)-1,2,5- Diazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4- Diazol-5(4H)-one hydroiodide

使3-(4-(2-疊氮基乙基胺基)-1,2,5-二唑-3-基)-4-(3-溴-4-氟苯基)-1,2,4-二唑-5(4H)-酮(80.0 g，0.194 mol)與甲醇(800 mL)混合。添加碘化鈉(175.0 g，1.17 mol)。將反應物在室溫下攪拌10分鐘。將氯三甲基矽烷(148 mL，1.17 mol)溶解於甲醇(100 mL)中且經30分鐘添加至反應物中。反應溫度升至42℃。將反應物在室溫下攪拌30分鐘。LCMS指示反應完成(M+H=386)。以水(900 mL)中之硫代硫酸鈉(190.0 g，1.20 mol)中止反應物。大量固體沈澱。藉由過濾(過濾速度緩慢)收集產物，以水(200 mL)沖洗且真空乾燥隔夜。將濾餅在乙酸乙酯(500 mL)中製成漿液歷時30分鐘。過濾(過濾速度緩慢)產物且在真空下乾燥整個週末，產生95 g灰白色固體。C12 H11 BrFN6 O3 (M+H)+ 之LCMS：m/z=384.9,386.9。1 H NMR(400 MHz,DMSO-d 6 )：δ8.12(m,4 H),7.76(m,1 H),7.58(t,J =8.7 Hz,1 H),6.78(t,J =6.1 Hz,1 H),3.51(dd,J =11.8,6.1 Hz,2 H),3.02(m,2 H)。3-(4-(2-azidoethylamino)-1,2,5- Diazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4- The oxazol-5(4H)-one (80.0 g, 0.194 mol) was mixed with methanol (800 mL). Sodium iodide (175.0 g, 1.17 mol) was added. The reaction was stirred at room temperature for 10 minutes. Chlorotrimethyldecane (148 mL, 1.17 mol) was dissolved in methanol (100 mL) and added to the reaction over 30 min. The reaction temperature rose to 42 °C. The reaction was stirred at room temperature for 30 minutes. LCMS indicated the completion of the reaction (M+H = 386). The reaction was quenched with sodium thiosulfate (190.0 g, 1.20 mol) in water (900 mL). A large amount of solid precipitated. The product was collected by filtration (slow filtration), rinsed with water (200 mL) and dried in vacuo overnight. The filter cake was slurried in ethyl acetate (500 mL) over 30 min. The product was filtered (slow filtration) and dried under vacuum over the weekend to yield 95 g of an off white solid. C 12 H 11 BrFN 6 O 3 (M + H) + The LCMS: m / z = 384.9,386.9. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.12 (m, 4 H), 7.76 (m, 1 H), 7.58 (t, J = 8.7 Hz, 1 H), 6.78 (t, J = 6.1 Hz, 1 H), 3.51 (dd, J = 11.8, 6.1 Hz, 2 H), 3.02 (m, 2 H).

實例23Example 23 4-({2-[(胺基磺醯基)胺基]乙基}胺基)- N -(3-溴-4-氟苯基)- N' -羥基-1,2,5- 二唑-3-甲醯亞胺酸胺之替代製備 4 - ({2 - [(sulfo amino acyl) amino] ethyl} amino) - N - (3- bromo-4-fluorophenyl) - N '- hydroxy-1,2,5 Alternative preparation of oxazol-3-carboxamide

步驟A：4-(3-溴-4-氟苯基)-3-(4-(2-羥基乙基胺基)-1,2,5-二唑-3-基)-1,2,4-二唑-5(4H)-酮Step A: 4-(3-Bromo-4-fluorophenyl)-3-(4-(2-hydroxyethylamino)-1,2,5- Diazol-3-yl)-1,2,4- Diazol-5(4H)-one

在0℃下，以使得溫度不超過10℃之速率向在22 L燒瓶中攪拌之4-(3-溴-4-氟苯基)-3-(4-(2-甲氧基乙基胺基)-1,2,5-二唑-3-基)-1,2,4-二唑-5(4H)-酮(可根據實例1步驟A-G 製備；1232 g，3.08 mol)於二氯甲烷(12 L)中之溶液中逐滴添加三溴化硼(354 mL，3.67 mL)。在冰上攪拌1小時後，以使得溫度不超過20℃之速率小心添加碳酸氫鈉飽和水溶液(2 L)(添加時間10分鐘)。將所得混合物轉移至50 L分液漏斗中，以水(10 L)稀釋，且使用固體碳酸氫鈉將水層之pH值自1調整至8。分離各層，且以水(10 L)洗滌有機層，且真空移除溶劑產生棕褐色固體(多輪處理24 mol，9.54 kg，定量產量)。將該物質在4個體積之7：1庚烷：乙酸乙酯(4×22 L燒瓶)中製成漿液，過濾，且乾燥產生呈棕褐色固體狀之標題化合物(8679 g，94%)。產物為羥基物質及相應溴物質之混合物。4-(3-Bromo-4-fluorophenyl)-3-(4-(2-methoxyethylamine) was stirred at 22 ° C in a 22 L flask at a rate such that the temperature did not exceed 10 ° C. Base)-1,2,5- Diazol-3-yl)-1,2,4- Addition of boron tribromide (354 mL, 3.67 mL) to a solution of oxazol-5(4H)-one (prepared according to the procedure of Example 1 AG ; 1232 g, 3.08 mol) in dichloromethane (12 L) . After stirring for 1 hour on ice, a saturated aqueous solution of sodium hydrogencarbonate (2 L) was carefully added at a rate such that the temperature did not exceed 20 ° C (addition time 10 minutes). The resulting mixture was transferred to a 50 L separatory funnel, diluted with water (10 L), and the pH of the aqueous layer was adjusted from 1 to 8 using solid sodium hydrogen carbonate. The layers were separated and the organic layer was washed with water (10 L) and solvent was evaporated in vacuo to afford a tan solid (24 m, 9. The material was slurried in EtOAc (EtOAc (EtOAc)EtOAc. The product is a mixture of hydroxyl species and corresponding bromine species.

步驟B：甲烷磺酸2-(4-(4-(3-溴-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基)-1,2,5-二唑-3-基胺基)乙酯Step B: 2-(4-(4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-methanesulfonate Diazol-3-yl)-1,2,5- Diazol-3-ylamino)ethyl ester

在室溫下經1小時向4-(3-溴-4-氟苯基)-3-{4-[(2-羥基乙基)胺基]-1,2,5-二唑-3-基}-1,2,4-二唑-5(4H )-酮(1.5 kg，3.9 mol，亦含有一些相應溴化合物)於乙酸乙酯(12 L)中之溶液中逐滴添加甲烷磺醯氯(185 mL，2.4 mol)。經45分鐘逐滴添加三乙胺(325 mL，2.3 mol)，在此期間反應溫度增至35℃。2小時後，以水(5 L)、鹽水(1 L)洗滌反應混合物，經硫酸鈉乾燥，與另外3份相同量之反應物合併，且真空移除溶劑產生呈棕褐色固體狀之所要產物(7600 g，定量產量，亦含有一些相應溴化合物，注意：刺激性粉塵！)。C13 H11 BrFN5 O6 SNa(M+Na)+ 之LCMS：m/z=485.9,487.9。1 H NMR(400 MHz,DMSO-d 6 )：δ8.08(dd,J =6.2,2.5 Hz,1 H),7.72(m,1 H),7.58(t,J =8.7 Hz,1 H),6.75(t,J =5.9 Hz,1 H),4.36(t,J =5.3 Hz,2 H),3.58(dd,J =11.2,5.6 Hz,2 H),3.18(s,3 H)。To 4-(3-bromo-4-fluorophenyl)-3-{4-[(2-hydroxyethyl)amino]-1,2,5- at room temperature over 1 hour Diazol-3-yl}-1,2,4- Methanesulfonium chloride (185 mL, 2.4 mol) was added dropwise to a solution of oxazol-5( 4H )-one (1.5 kg, 3.9 mol, also containing some corresponding bromine compound) in ethyl acetate (12 L) . Triethylamine (325 mL, 2.3 mol) was added dropwise over 45 minutes, during which time the reaction temperature was increased to 35 °C. After 2 hours, the reaction mixture was washed with water (5 L), brine (1 L), dried over sodium sulfate, and then combined with three additional portions of the mixture, and the solvent was removed in vacuo to give the desired product as a tan solid. (7600 g, quantitative yield, also contains some corresponding bromine compounds, note: irritating dust!). C 13 H 11 BrFN 5 O 6 SNa (M + Na) + The LCMS: m / z = 485.9,487.9. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.08 (dd, J = 6.2, 2.5 Hz, 1 H), 7.72 (m, 1 H), 7.58 (t, J = 8.7 Hz, 1 H) , 6.75 (t, J = 5.9 Hz, 1 H), 4.36 (t, J = 5.3 Hz, 2 H), 3.58 (dd, J = 11.2, 5.6 Hz, 2 H), 3.18 (s, 3 H).

步驟C：3-(4-(2-疊氮基乙基胺基)-1,2,5-二唑-3-基)-4-(3-溴-4-氟苯基)-1,2,4-二唑-5(4H)-酮Step C: 3-(4-(2-azidoethylamino)-1,2,5- Diazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4- Diazol-5(4H)-one

向在22 L燒瓶中攪拌之甲烷磺酸2-({4-[4-(3-溴-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}胺基)乙酯(2.13 kg，4.6 mol，亦含有一些相應溴化合物)於二甲基甲醯胺(4 L)中之溶液中添加疊氮化鈉(380 g，5.84 mol)。將反應物在50℃下加熱6小時，傾注於冰/水(8 L)中，且以1：1乙酸乙酯：庚烷(20 L)萃取。以水(5 L)及鹽水(5 L)洗滌有機層，且真空移除溶液產生呈棕褐色固體狀之所要產物(1464 g，77%)。C12 H8 BrFN8 O3 Na(M+Na)+ 之LCMS：m/z=433.0,435.0。1 H NMR(DMSO-d6 ,400 MHz)：δ8.08(dd,J =6.2,2.5Hz,1H),7.72(m,1H),7.58(t,J =8.7Hz,1H),6.75(t,J =5.7Hz,1H),3.54(t,J =5.3Hz,2H),3.45(dd,J =11.1,5,2Hz,2H)。2-({4-[4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4 methanesulfonate) stirred in a 22 L flask - Diazol-3-yl]-1,2,5- Adding sodium azide (380 g, oxazol-3-yl}amino)ethyl ester (2.13 kg, 4.6 mol, also containing some corresponding bromine compound) in dimethylformamide (4 L) 5.84 mol). The reaction was heated at 50 &lt;0&gt;C for 6 h, poured over ice/water (8L) andEtOAcEtOAc The organic layer was washed with water (5 L) and brine (5L). C 12 H 8 BrFN 8 O 3 Na (M + Na) + The LCMS: m / z = 433.0,435.0. 1 H NMR (DMSO-d 6 , 400 MHz): δ 8.08 (dd, J = 6.2, 2.5 Hz, 1H), 7.72 (m, 1H), 7.58 (t, J = 8.7 Hz, 1H), 6.75 ( t, J = 5.7 Hz, 1H), 3.54 (t, J = 5.3 Hz, 2H), 3.45 (dd, J = 11.1, 5, 2 Hz, 2H).

步驟D：3-{4-[(2-胺基乙基)胺基]-1,2,5-二唑-3-基}-4-(3-溴-4-氟苯基)-1,2,4-二唑-5(4H )-酮鹽酸鹽Step D: 3-{4-[(2-Aminoethyl)amino]-1,2,5- Diazol-3-yl}-4-(3-bromo-4-fluorophenyl)-1,2,4- Diazol-5(4 H )-one hydrochloride

步驟D部分1：2-(4-(4-(3-溴-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基)-1,2,5-二唑-3-基胺基)乙基胺基甲酸第三丁酯Step D Part 1: 2-(4-(4-(3-Bromo-4-fluorophenyl)-5-sidedoxy-4,5-dihydro-1,2,4- Diazol-3-yl)-1,2,5- Tert-butyl 3-oxazol-3-ylamino)ethylaminocarbamate

向甲醇(6 L)中之3-{4-[(2-疊氮基乙基)胺基]-1,2,5-二唑-3-基}-4-(3-溴-4-氟苯基)-1,2,4-二唑-5(4H )-酮(500 g，1.22 mol)中添加碘化鈉(1080 g，7,2 mol)。將混合物攪拌30分鐘，其間觀測到溫和放熱。以使得溫度不超過35℃之速率、以甲醇(1 L)中之溶液的形式逐滴添加氯三甲基矽烷(930 mL，7.33 mol)，且將反應物在環境溫度下攪拌3.5小時。以五水合硫代硫酸鈉於水(約1.5 L)中之33重量%溶液中和反應物，以水(4 L)稀釋且以固體碳酸鉀(250 g，以數小份添加：注意發泡)小心地將pH值調整至9。添加二鹽酸二-第三丁酯(318 g，1.45 mol)且將反應物在室溫下攪拌。經4小時以50 g數份添加額外碳酸鉀(200 g)以確保pH值仍為9或高於9。在室溫下攪拌隔夜後，過濾固體，以水(2 L)濕磨，且接著以MTBE(1.5 L)濕磨。總共進行11輪處理(5.5 kg，13.38 mol)。以1：1 THF：二氯甲烷(24 L，在20 L旋轉蒸發器燒瓶中進行4輪處理，50℃，1小時)濕磨經合併之固體，過濾且以二氯甲烷(每輪3 L)洗滌產生灰白色固體。在55℃下將粗物質溶解於四氫呋喃(5 mL/g)中，以脫色碳(2重量%)及矽膠(2重量%)處理，經由矽藻土熱過濾以產生呈灰白色固體狀之產物(5122 g)。真空濃縮經合併之MTBE、THF及二氯甲烷濾液且層析(2 kg矽膠，具有0-100%乙酸乙酯梯度之庚烷，30 L)以產生更多產物(262 g)。將經合併之2-(4-(4-(3-溴-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基)-1,2,5-二唑-3-基胺基)乙基胺基甲酸第三丁酯固體在對流烘箱中乾燥至恆重(5385 g，83%)。3-{4-[(2-azidoethyl)amino]-1,2,5- to methanol (6 L) Diazol-3-yl}-4-(3-bromo-4-fluorophenyl)-1,2,4- Sodium iodide (1080 g, 7, 2 mol) was added to the oxazol-5( 4H )-one (500 g, 1.22 mol). The mixture was stirred for 30 minutes during which a mild exotherm was observed. Chlorotrimethylnonane (930 mL, 7.33 mol) was added dropwise in the form of a solution in methanol (1 L) at a rate such that the temperature did not exceed 35 ° C, and the reaction was stirred at ambient temperature for 3.5 hours. The reaction was neutralized with a 33% by weight solution of sodium thiosulfate pentahydrate in water (about 1.5 L), diluted with water (4 L) and added in solid potassium carbonate (250 g, in small portions: note foaming ) Carefully adjust the pH to 9. Di-tert-butyl dihydrochloride (318 g, 1.45 mol) was added and the reaction was stirred at room temperature. Additional potassium carbonate (200 g) was added in 50 g portions over 4 hours to ensure that the pH was still 9 or above 9. After stirring overnight at room temperature, the solid was filtered, wet-purified with water (2L), and then wet-milled with MTBE (1.5 L). A total of 11 rounds of treatment (5.5 kg, 13.38 mol) were performed. The combined solids were wet-milled in 1:1 THF: dichloromethane (24 L, 4 rounds in a 20 L rotary evaporator flask, 50 ° C, 1 hour), filtered and taken in dichloromethane (3 L per round) Washing produces an off-white solid. The crude material was dissolved in tetrahydrofuran (5 mL/g) at 55 ° C, treated with decoloring carbon (2% by weight) and silica gel (2% by weight), and filtered through celite to give a product as an off-white solid ( 5122 g). The combined MTBE, THF and dichloromethane filtrates were concentrated in vacuo and chromatographed (2 g EtOAc EtOAc EtOAc EtOAc The combined 2-(4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4- Diazol-3-yl)-1,2,5- The tert-butyl solid of oxazol-3-ylamino)ethylcarbamate was dried to constant weight (5385 g, 83%) in a convection oven.

步驟D部分2：3-{4-[(2-胺基乙基)胺基]-1,2,5-二唑-3-基}-4-(3-溴-4-氟苯基)-1,2,4-二唑-5(4H )-酮鹽酸鹽Step D Part 2: 3-{4-[(2-Aminoethyl)amino]-1,2,5- Diazol-3-yl}-4-(3-bromo-4-fluorophenyl)-1,2,4- Diazol-5(4 H )-one hydrochloride 方法A：Method A:

將氯化氫(1,4-二烷中之4 N溶液，4 L，16 mol)饋入22 L燒瓶中。經10分鐘數份添加固體形式之[2-({4-[4-(3-溴-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}胺基)乙基]胺基甲酸第三丁酯(2315 g，4.77 mol)。在室溫下攪拌漿液且逐漸變為不能攪拌之黏稠糊狀物。在室溫下擱置隔夜後，將糊狀物在乙酸乙酯(10 L)中製成漿液，過濾，在乙酸乙酯(5 L)中再製成漿液，過濾且乾燥至恆重以產生呈白色固體狀之所要產物(與其他處理合併，饋入5 kg起始物質，4113 g，95%)。C12 H11 BrFN6 O3 (M+H)+ 之LCMS：m/z=384.9,386.9。1 H NMR(400 MHz,DMSO-d 6 )：δ8.12(m,4 H),7.76(m,1 H),7.58(t,J =8.7 Hz,1 H),6.78(t,J =6.1 Hz,1 H),3.51(dd,J =11.8,6.1 Hz,2 H),3.02(m,2 H)。Hydrogen chloride (1,4-di The 4 N solution in the alkane, 4 L, 16 mol) was fed into a 22 L flask. [2-({4-[4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-) was added in solid form over 10 minutes. Diazol-3-yl]-1,2,5- Tert-butyl 3-oxazol-3-yl}amino)ethyl]carbamic acid (2315 g, 4.77 mol). The slurry was stirred at room temperature and gradually became a viscous paste that could not be stirred. After standing overnight at room temperature, the syrup was slurried in ethyl acetate (10 L), filtered, and re-slued in ethyl acetate (5 L), filtered and dried to constant weight to yield The desired product was obtained as a white solid ( combined with other treatments, 5 kg starting material, 4113 g, 95%). C 12 H 11 BrFN 6 O 3 (M + H) + The LCMS: m / z = 384.9,386.9. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.12 (m, 4 H), 7.76 (m, 1 H), 7.58 (t, J = 8.7 Hz, 1 H), 6.78 (t, J = 6.1 Hz, 1 H), 3.51 (dd, J = 11.8, 6.1 Hz, 2 H), 3.02 (m, 2 H).

方法B：Method B:

在室溫下將[2-({4-[4-(3-溴-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}胺基)乙基]胺基甲酸第三丁酯(5000 g)添加至異丙醇(20 L)及1,4-二烷中之4 N HCl(10 L)的混合物中。將批料加熱至40-45℃且保持1小時。在40-45℃下向批料中添加乙酸乙酯且保持2.5小時。HPLC指示反應完成後，向批料中添加庚烷(10 L)。將批料冷卻至25℃。藉由過濾分離產物且以乙酸乙酯(3×5.0 L)洗滌濕濾餅。在20℃下、在真空烘箱中乾燥產物產生4344 g(93.4%產率)標題化合物。此批次之LC-MS、1 H及13 C NMR及HPLC數據與藉由方法A製備之產物的彼等數據相同。[2-({4-[4-(3-Bromo-4-fluorophenyl)-5- pendantoxy-4,5-dihydro-1,2,4- at room temperature Diazol-3-yl]-1,2,5- Addition of tert-butyl 3-oxazol-3-yl}amino)ethyl]carbamate (5000 g) to isopropanol (20 L) and 1,4-di In a mixture of 4 N HCl (10 L) in the alkane. The batch was heated to 40-45 ° C for 1 hour. Ethyl acetate was added to the batch at 40-45 °C for 2.5 hours. After HPLC indicated the completion of the reaction, heptane (10 L) was added to the batch. The batch was cooled to 25 °C. The product was isolated by filtration and washed with ethyl acetate (3.times.5 L). The product was dried in a vacuum oven at 20 °C to yield 4344 g (93.4% yield) of title compound. The LC-MS, 1 H and 13 C NMR and HPLC data for this batch were identical to those for the product prepared by Method A.

步驟E：({[2-({4-[4-(3-溴-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}胺基)乙基]胺基}磺醯基)胺基甲酸第三丁酯Step E: ({[2-({4-[4-(3-Bromo-4-fluorophenyl)-5-yloxy-4,5-dihydro-1,2,4- Diazol-3-yl]-1,2,5- Diazol-3-yl}amino)ethyl]amino}sulfonyl) carboxylic acid tert-butyl ester

將氯磺醯異氰酸酯[Aldrich，產品號142662](149 mL，1.72 mol)及二氯甲烷(1.5 L)饋入5 L圓底燒瓶中且使用冰浴冷卻至2℃。以使得溫度不超過10℃之速率逐滴添加二氯甲烷(200 mL)中之第三丁醇(162 mL，1.73 mol)。將所得溶液在室溫下攪拌30-60分鐘以產生[氯磺醯基]胺基甲酸第三丁酯。Chlorosulfonium isocyanate [Aldrich, product number 142662] (149 mL, 1.72 mol) and dichloromethane (1.5 L) were fed to a 5 L round bottom flask and cooled to 2 ° C using an ice bath. The third butanol (162 mL, 1.73 mol) in dichloromethane (200 mL) was added dropwise at a rate such that the temperature did not exceed 10 °C. The resulting solution was stirred at room temperature for 30-60 minutes to give [chlorosulfonyl] carbamic acid tert-butyl ester.

將3-{4-[(2-胺基乙基)胺基]-1,2,5-二唑-3-基}-4-(3-溴-4-氟苯基)-1,2,4-二唑-5(4H )-酮鹽酸鹽(661 g，1.57 mol)及8.5 L二氯甲烷饋入22 L燒瓶中。以冰/鹽浴冷卻至-15℃之後，以使得溫度不超過-10℃之速率添加[氯磺醯基]胺基甲酸第三丁酯溶液(如上文所述製備)(添加時間7分鐘)。攪拌10分鐘後，以使得溫度不超過-5℃之速率添加三乙胺(1085 mL，7.78 mol)(添加時間10分鐘)。移除冷浴，使反應物溫至10℃，分成兩份，且以10%濃鹽酸(每份4.5 L)中和。將各份轉移至50 L分液漏斗中且以乙酸乙酯稀釋以完全溶解白色固體(約25 L)。分離各層，且以水(5 L)、鹽水(5 L)洗滌各層且真空移除溶劑產生灰白色固體。以MTBE(2×1.5 L)濕磨固體且乾燥至恆重產生白色固體。以此方式處理總共4113 g起始物質(5409 g，98%)。1 H NMR(400 MHz,DMSO-d 6 )：δ10.90(s,1 H),8.08(dd,J =6.2,2.5 Hz,1 H),7.72(m,1 H),7.59(t,J =8.6 Hz,1 H),6.58(t,J =5.7 Hz,1 H),3.38(dd,J =12.7,6.2 Hz,2 H),3.10(dd,J =12.1,5.9 Hz,2 H),1.41(s,9 H)。3-{4-[(2-Aminoethyl)amino]-1,2,5- Diazol-3-yl}-4-(3-bromo-4-fluorophenyl)-1,2,4- The oxazol-5( 4H )-one hydrochloride (661 g, 1.57 mol) and 8.5 L of dichloromethane were fed into a 22 L flask. After cooling to -15 ° C in an ice/salt bath, a solution of [chlorosulfonyl] carbamic acid tert-butyl ester (prepared as described above) was added at a rate such that the temperature did not exceed -10 ° C (addition time 7 minutes) . After stirring for 10 minutes, triethylamine (1085 mL, 7.78 mol) was added at a rate such that the temperature did not exceed -5 ° C (addition time 10 minutes). The cold bath was removed and the reaction was warmed to 10 ° C, taken in two portions and neutralized with 10% concentrated hydrochloric acid (4.5 L each). The fractions were transferred to a 50 L separatory funnel and diluted with ethyl acetate to dissolve a white solid (~25L). The layers were separated and the layers were washed with water (5 L), brine (5L) The solid was wet milled with MTBE (2 x 1.5 L) and dried to constant weight to yield a white solid. A total of 4113 g of starting material (5409 g, 98%) was treated in this way. 1 H NMR (400 MHz, DMSO- d 6 ): δ 10.90 (s, 1 H), 8.08 (dd, J = 6.2, 2.5 Hz, 1 H), 7.72 (m, 1 H), 7.59 (t, J = 8.6 Hz, 1 H), 6.58 (t, J = 5.7 Hz, 1 H), 3.38 (dd, J = 12.7, 6.2 Hz, 2 H), 3.10 (dd, J = 12.1, 5.9 Hz, 2 H ), 1.41 (s, 9 H).

步驟F：N -[2-({4-[4-(3-溴-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}胺基)乙基]磺醯胺Step F: N- [2-({4-[4-(3-Bromo-4-fluorophenyl)-5- pendantoxy-4,5-dihydro-1,2,4- Diazol-3-yl]-1,2,5- Diazol-3-yl}amino)ethyl]sulfonamide

方法A：使用三氟乙酸Method A: Using Trifluoroacetic Acid

經10分鐘向含有98：2三氟乙酸：水(8.9 L)之22 L燒瓶中數份添加({[2-({4-[4-(3-溴-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}胺基)乙基]胺基}磺醯基)胺基甲酸第三丁酯(1931 g，3.42 mol)。將所得混合物在室溫下攪拌1.5小時，真空移除溶劑且追加二氯甲烷(2 L)。以新鮮98：2三氟乙酸：水(8.9 L)第二次處理所得固體，在40-50℃下加熱1小時，真空移除溶劑且追加二氯甲烷(3×2 L)。在50℃下、在真空乾燥烘箱中乾燥所得白色固體隔夜。以此方式總共處理5409 g(4990 g，定量產量)。C12 H12 BrFN7 O5 S(M+H)+ 之LCMS：m/z=463.9,465.9。1 H NMR(400 MHz,DMSO-d 6 )：δ8.08(dd,J =6.2,2.5 Hz,1 H),7.72(m,1 H),7.59(t,J =8.7 Hz,1 H),6.67(t,J =5.9 Hz,1H),6.52(t,J =6.0 Hz,1 H),3.38(dd,J =12.7,6.3 Hz,2 H),3.11(dd,J =12.3,6.3 Hz)。({[2-({4-[4-(3-Bromo-4-fluorophenyl)-5) was added in several portions to a 22 L flask containing 98:2 trifluoroacetic acid: water (8.9 L) over 10 min. -Sideoxy-4,5-dihydro-1,2,4- Diazol-3-yl]-1,2,5- Diazol-3-yl}amino)ethyl]amino}sulfonyl) carbamic acid tert-butyl ester (1931 g, 3.42 mol). The resulting mixture was stirred at room temperature for 1.5 hr. The solid was treated a second time with fresh 98:2 trifluoroacetic acid: water (8.9L). EtOAc was evaporated from EtOAc. The resulting white solid was dried overnight at 50 ° C in a vacuum drying oven. A total of 5409 g (4990 g, quantitative yield) was processed in this way. C 12 H 12 BrFN 7 O 5 S (M + H) + The LCMS: m / z = 463.9,465.9. 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.08 (dd, J = 6.2, 2.5 Hz, 1 H), 7.72 (m, 1 H), 7.59 (t, J = 8.7 Hz, 1 H) , 6.67 (t, J = 5.9 Hz, 1H), 6.52 (t, J = 6.0 Hz, 1 H), 3.38 (dd, J = 12.7, 6.3 Hz, 2 H), 3.11 (dd, J = 12.3, 6.3 Hz).

方法B：使用鹽酸Method B: Using hydrochloric acid

向({[2-({4-[4-(3-溴-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}胺基)乙基]胺基}磺醯基)胺基甲酸第三丁酯(4500 g)於異丙醇(9 L)中之溶液中添加二烷中之4 N HCl(8.0 L)。將反應混合物加熱至40-45℃且在此溫度下保持約5小時。反應完成(如HPLC分析所指示)後，向反應混合物中添加庚烷(72 L)。將所得混合物加熱至68℃且在此溫度下保持1小時。將批料冷卻至約23℃。藉由過濾收集固體產物。以庚烷(16 L)與異丙醇(1.2 L)之混合物洗滌濕濾餅且在抽吸下、在過濾漏斗上乾燥。在約43℃下將粗產物溶解於乙酸乙酯(10.8 L)中。經15分鐘向乙酸乙酯溶液中添加庚烷(32.4 L)。將批料加熱至70℃且在此溫度下保持1小時。將批料冷卻至21℃且藉由過濾收集固體產物。以庚烷(14.4 L)洗滌濕濾餅且在抽吸下、在過濾漏斗上乾燥。產物之產量為3034 g。此批次之LC-MS、1 H及13 C NMR及HPLC數據與藉由方法A製備之產物的彼等數據相同。To ({[2-({4-[4-(3-Bromo-4-fluorophenyl)-5-yloxy-4,5-dihydro-1,2,4- Diazol-3-yl]-1,2,5- Addition of a solution of tert-butyl-3-oxa}amino)ethyl]amino}sulfonyl) carbamic acid tert-butyl ester (4500 g) in isopropanol (9 L) 4 N HCl (8.0 L) in the alkane. The reaction mixture was heated to 40-45 ° C and maintained at this temperature for about 5 hours. After completion of the reaction (as indicated by HPLC analysis), heptane (72 L) was added to the reaction mixture. The resulting mixture was heated to 68 ° C and maintained at this temperature for 1 hour. The batch was cooled to about 23 °C. The solid product was collected by filtration. The wet cake was washed with a mixture of heptane (16 L) and isopropanol (1.2 L) and dried under suction on a filter funnel. The crude product was dissolved in ethyl acetate (10.8 L) at about 43 °C. Heptane (32.4 L) was added to the ethyl acetate solution over 15 minutes. The batch was heated to 70 ° C and held at this temperature for 1 hour. The batch was cooled to 21 ° C and the solid product was collected by filtration. The wet cake was washed with heptane (14.4 L) and dried under suction on a filter funnel. The yield of the product was 3034 g. The LC-MS, 1 H and 13 C NMR and HPLC data for this batch were identical to those for the product prepared by Method A.

步驟G：(Z) -4-({2-[(胺基磺醯基)胺基]乙基}胺基)-N -(3-溴-4-氟苯基)-N' -羥基-1,2,5-二唑-3-甲醯亞胺醯胺Step G: (Z) -4 - ( {2 - [( sulfo amino acyl) amino] ethyl} amino) - N - (3- bromo-4-fluorophenyl) - N '- hydroxy - 1,2,5- Diazole-3-carboxamide 方法A：Method A:

向在22 L燒瓶中攪拌之含有殘餘量之三氟乙酸的N -[2-({4-[4-(3-溴-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}胺基)乙基]磺醯胺(2.4 mol)之粗混合物中添加THF(5 L)。使用冰浴將所得溶液冷卻至0℃且以使得溫度不超過10℃之速率添加2 N NaOH(4 L)。在環境溫度下攪拌3小時之後(LCMS指示無剩餘之起始物質)，以濃鹽酸(約500 mL)將pH值調整至3-4。真空移除THF，且以乙酸乙酯(15 L)萃取所得混合物。以水(5 L)、鹽水(5 L)洗滌有機層，且真空移除溶劑產生固體。以MTBE(2×2 L)濕磨固體，與另外三份相同量之反應物合併，且在對流烘箱中乾燥隔夜產生白色固體(3535 g)。將固體再結晶(3×22 L燒瓶，2：1去離子超濾水：乙醇，每個燒瓶14.1 L)且在50℃對流烘箱中乾燥至恆重以產生呈灰白色固體狀之標題化合物(3290 g，78%)。C11 H14 BrFN7 O4 S(M+H)+ 之LCMS：m/z=437.9,439.9。1 H NMR(400 MHz,DMSO-d 6 )：δ11.51(s,1 H),8.90(s,1 H),7.17(t,J =8.8 Hz,1 H),7.11(dd,J =6.1,2.7 Hz,1 H),6.76(m,1 H),6.71(t,J =6.0 Hz,1 H),6.59(s,2 H),6.23(t,J =6.1 Hz,1 H),3.35(dd,J =10.9,7.0 Hz,2 H),3.10(dd,J =12.1,6.2 Hz,2 H)。X射線結晶分析測定標題化合物關於肟官能基之碳-氮雙鍵(C=N)採用Z 構型(Z 型異構體)。 N- [2-({4-[4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-) containing a residual amount of trifluoroacetic acid in a 22 L flask. Dihydro-1,2,4- Diazol-3-yl]-1,2,5- To the crude mixture of oxazol-3-yl}amino)ethyl]sulfonamide (2.4 mol) was added THF (5 L). The resulting solution was cooled to 0 °C using an ice bath and 2 N NaOH (4 L) was added at such a rate that the temperature did not exceed 10 °C. After stirring at ambient temperature for 3 hours (LCMS indicated no starting material remaining), the pH was adjusted to 3-4 with concentrated hydrochloric acid (approximately 500 mL). The THF was removed in vacuo and the mixture was extracted with ethyl acetate (15L). The organic layer was washed with water (5 L), brine (5 L) and solvent was evaporated in vacuo. The solid was wet milled with MTBE (2 x 2 L), combined with three additional portions of the mixture and dried in a convection oven overnight to yield a white solid (3535 g). The solid was recrystallized (3×22 L flask, 2:1 deionized ultrafiltration water: ethanol, 14.1 L per flask) and dried to constant weight in a 50 ° C convection oven to give the title compound (3290 g, 78%). C 11 H 14 BrFN 7 O 4 S (M + H) + The LCMS: m / z = 437.9,439.9. 1 H NMR (400 MHz, DMSO- d 6 ): δ 11.51 (s, 1 H), 8.90 (s, 1 H), 7.17 (t, J = 8.8 Hz, 1 H), 7.11 (dd, J = 6.1, 2.7 Hz, 1 H), 6.76 (m, 1 H), 6.71 (t, J = 6.0 Hz, 1 H), 6.59 (s, 2 H), 6.23 (t, J = 6.1 Hz, 1 H) , 3.35 (dd, J = 10.9, 7.0 Hz, 2 H), 3.10 (dd, J = 12.1, 6.2 Hz, 2 H). X-ray crystallographic analysis determined the carbon-nitrogen double bond (C=N) of the title compound with respect to the oxime functional group in the Z configuration ( Z isomer).

方法B：Method B:

向THF(6.0 L)中添加N -[2-({4-[4-(3-溴-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-二唑-3-基]-1,2,5-二唑-3-基}胺基)乙基]磺醯胺(1500 g)且將批料冷卻至2℃。在2℃下向批料中添加三氟乙酸(0.006 L)，隨後在0-2℃下添加氫氧化鈉水溶液(4.8 L水中之384 g固體NaOH)。將批料溫至約16℃且保持5小時。反應完成(如HPLC指示)後，添加濃鹽酸(0.7 L)將批料之pH值調整至3-4。藉由在減壓下蒸餾自批料移除約4 L溶劑。將批料添加至乙酸乙酯(18.0 L)中且將兩相混合物攪拌15分鐘。依序以水(6.0 L)及鹽水(6.0 L)洗滌有機層。經無水硫酸鎂乾燥有機溶液。過濾硫酸鎂且在減壓下將濾液蒸乾。向所得固體中添加MTBE(3.0 L)且將漿液攪拌15分鐘。藉由過濾分離固體產物。依序以MTBE(1.2 L)及庚烷(1.2 L)洗滌濾餅。在抽吸下、在過濾漏斗上乾燥固體產生1416 g(87.9%)產物。藉由在17℃下、在MTBE(9.6 L)中再製成漿液歷時2小時來進一步純化產物(2440 g，以兩批獲得)。將批料冷卻至6℃歷時30分鐘。藉由過濾收集固體產物且依序以MTBE(3.6 L)及庚烷(1.2 L)洗滌濕濾餅。在真空烘箱中、在20℃下乾燥產物，產生1962 g標題化合物(81.7%產率)。此批次之LC-MS、1 H及13 C NMR及HPLC數據與藉由方法A製備之產物的彼等數據相同。Add N- [2-({4-[4-(3-bromo-4-fluorophenyl)-5- pendantoxy-4,5-dihydro-1,2,4 to THF (6.0 L) - Diazol-3-yl]-1,2,5- Azoxa-3-yl}amino)ethyl]sulfonamide (1500 g) and the batch was cooled to 2 °C. Trifluoroacetic acid (0.006 L) was added to the batch at 2 ° C, followed by the addition of aqueous sodium hydroxide (384 g of solid NaOH in 4.8 L of water) at 0-2 °C. The batch was warmed to about 16 ° C for 5 hours. After completion of the reaction (as indicated by HPLC), concentrated hydrochloric acid (0.7 L) was added to adjust the pH of the batch to 3-4. About 4 L of solvent was removed from the batch by distillation under reduced pressure. The batch was added to ethyl acetate (18.0 L) and the mixture was stirred 15 min. The organic layer was washed sequentially with water (6.0 L) and brine (6.0 L). The organic solution was dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered and the filtrate was evaporated to dryness under reduced pressure. MTBE (3.0 L) was added to the obtained solid and the slurry was stirred for 15 min. The solid product was isolated by filtration. The filter cake was washed sequentially with MTBE (1.2 L) and heptane (1.2 L). Drying the solid on a filter funnel under suction gave 1416 g (87.9%) of product. The product was further purified (2440 g, obtained in two batches) by reslurrying in MTBE (9.6 L) for 2 hours at 17 °C. The batch was cooled to 6 ° C for 30 minutes. The solid product was collected by filtration and washed sequentially with MTBE (3.6 L) and heptane (1.2 L). The product was dried in a vacuum oven at 20 ° C to yield 1962 g of the title compound (81.7% yield). The LC-MS, 1 H and 13 C NMR and HPLC data for this batch were identical to those for the product prepared by Method A.

實例24Example 24 化合物數據Compound data

下表2中總結實例1-19之化合物的所選物理及生物活性數據。IC50 數據來自實例A中提供之檢定。Selected physical and biological activity data for the compounds of Examples 1-19 are summarized in Table 2 below. The IC 50 data is derived from the assay provided in Example A.

實例25Example 25 化合物數據Compound data

下表3中提供實例20及21之化合物的IDO IC50 數據(參見實例A)。Table 3 below provides an example of compounds 20 and 21 of IDO IC 50 data (see Example A).

實例26Example 26 NMR數據NMR data

下表4中提供實例1-21之化合物的1 H NMR數據(Varian Inova 500光譜儀、Mercury 400光譜儀或Varian(或Mercury)300光譜儀)。 1 H NMR data for the compounds of Examples 1-21 (Varian Inova 500 spectrometer, Mercury 400 spectrometer or Varian (or Mercury) 300 spectrometer) are provided in Table 4 below.

實例A：人類吲哚胺2,3-雙加氧酶(IDO)酶檢定Example A: Human indoleamine 2,3-dioxygenase (IDO) enzyme assay

在大腸桿菌(E.coli )中表現具有N末端His標記之人類吲哚胺2,3-雙加氧酶(IDO)且純化至同種。IDO催化色胺酸之吲哚核之吡咯環的氧化性裂解以產生N '-甲醯基犬尿胺酸。該等檢定係如文獻中所述、在室溫下、在50 mM磷酸鉀緩衝液(pH 6.5)中、在20 mM抗壞血酸鹽、5 μM亞甲基藍及0.2 mg/mL過氧化氫酶存在下、使用95 nM IDO及2 mM D-Trp進行。藉由以321 nm連續追蹤因N '-甲醯基犬尿胺酸形成所致之吸光度增加來記錄初始反應速率(參見：Sono,M.等人，1980,J.Biol.Chem .255,1339-1345)。Human guanamine 2,3-dioxygenase (IDO) with an N-terminal His tag was expressed in E. coli and purified to the same species. IDO catalyzes the oxidative cleavage of the pyrrole ring of the purine nucleus of tryptophan to produce N' -formyl kynurenine. These assays were performed as described in the literature at room temperature in 50 mM potassium phosphate buffer (pH 6.5) in the presence of 20 mM ascorbate, 5 μM methylene blue and 0.2 mg/mL catalase. 95 nM IDO and 2 mM D-Trp were performed. By continuously tracking at 321 nm due to N '- methyl acyl lysine kynurenic the increase in absorbance due to formation of a recording the initial reaction rate (see: Sono, M, et al., 1980, J.Biol.Chem .255,1339. -1345).

實例B：在基於海拉細胞之吲哚胺2,3-雙加氧酶(IDO)/犬尿胺酸檢定中測定抑制劑活性Example B: Determination of inhibitor activity in a Hella cell-based indoleamine 2,3-dioxygenase (IDO)/kynurenine assay

自美國菌種保存中心(American Type Tissue Culture Collection)(ATCC,Manassas,VA)獲得海拉細胞(CCL-2號)且常規保存於具有2 mM L-麩醯胺酸及經調整含有1.5 g/L碳酸氫鈉、0.1 mM非必需胺基酸、1 mM丙酮酸鈉及10%胎牛血清(均來自Invitrogen)之Earle's BSS的最低必需培養基(eagle)中。將細胞在補充有5% CO2 之加濕恆溫箱中、在37℃下保存。如下進行檢定：將海拉細胞以每孔5×103 之密度接種於96孔培養盤中且培養隔夜。次日，向細胞中添加IFN-y(50 ng/mL最終濃度)及化合物之連續稀釋液(培養基總體積為200 μL)。培育48小時後，將每孔140 μL上清液轉移至新96孔盤中。將10 μL之6.1 N三氯乙酸(#T0699,Sigma)混入各孔中且在50℃下培育30分鐘以使藉由吲哚胺2,3-雙加氧酶所產生之N -甲醯基犬尿胺酸水解為犬尿胺酸。隨後將反應混合物以2500 rpm離心10分鐘以移除沈積物。將每孔100 μL上清液轉移至另一96孔盤中且與100 μl於乙酸中之2%(w/v)對-二甲基胺基苯甲醛(#15647-7,Sigma-Aldrich)混合。使用SPECTRAmax 250微盤讀取器(Molecular Devices)、在480 nm下量測犬尿胺酸所產生之黃色。L-犬尿胺酸(#K8625,Sigma)用作標準物。將標準物(240 μM、120 μM、60 μM、30 μM、15 μM、7.5 μM、3.75 μM、1.87 μM)製備於100 μL培養基中且與等體積之2%(w/v)對-二甲基胺基苯甲醛混合。在個別濃度下測定抑制百分比且獲得雙重複檢定之平均值。藉由使用非線性回歸法分析數據以產生IC50 值(Prism Graphpad)。參看：Takikawa O等人，1988,J.Biol.Chem., 263(4)：2041-8。HeLa cells (CCL-2) were obtained from the American Type Tissue Culture Collection (ATCC, Manassas, VA) and routinely stored with 2 mM L-glutamic acid and adjusted to contain 1.5 g/ L sodium bicarbonate, 0.1 mM non-essential amino acid, 1 mM sodium pyruvate and 10% fetal bovine serum (both from Invitrogen) in Earle's BSS minimum essential medium (eagle). The cells were stored at 37 ° C in a humidified incubator supplemented with 5% CO 2 . The assay was performed as follows: HeLa cells were seeded in a 96-well culture dish at a density of 5 x 10 3 per well and cultured overnight. On the next day, IFN-y (50 ng/mL final concentration) and serial dilutions of the compound (200 μL total medium volume) were added to the cells. After 48 hours of incubation, 140 μL of supernatant per well was transferred to a new 96-well plate. 10 μL of 6.1 N trichloroacetic acid (#T0699, Sigma) was mixed into each well and incubated at 50 ° C for 30 minutes to produce N -methyl thiol by guanamine 2,3-dioxygenase. Canine urinary acid hydrolysis is kynurenine. The reaction mixture was then centrifuged at 2500 rpm for 10 minutes to remove deposits. 100 μL of supernatant per well was transferred to another 96-well plate with 100 μl of 2% (w/v) p-dimethylaminobenzaldehyde in acetic acid (#15647-7, Sigma-Aldrich) mixing. The yellow color produced by kynurenine was measured at 480 nm using a SPECTRAmax 250 microdisk reader (Molecular Devices). L-canine uric acid (#K8625, Sigma) was used as a standard. Standards (240 μM, 120 μM, 60 μM, 30 μM, 15 μM, 7.5 μM, 3.75 μM, 1.87 μM) were prepared in 100 μL of medium with an equal volume of 2% (w/v) p-dimethyl The amino-aminobenzaldehyde is mixed. The percent inhibition was determined at individual concentrations and the average of the double replicate assays was obtained. The data was analyzed by using nonlinear regression to generate an IC 50 value (Prism Graphpad). See: Takikawa O et al, 1988, J. Biol. Chem., 263(4): 2041-8.

實例C：測定IDO抑制劑對表現IDO之樹突狀細胞所抑制之T細胞增殖的作用Example C: Determination of the effect of IDO inhibitors on T cell proliferation inhibited by dendritic cells expressing IDO

藉由白細胞透入法、自人類外周單核細胞收集單核細胞。隨後使用補充有10%胎牛血清及2 mM L-麩醯胺酸(均來自Invitrogen)之RPMI 1640培養基，以每孔1×106 個細胞之密度將單核細胞接種於96孔盤中。在37℃下培養隔夜後，黏附細胞持留於培養盤上。隨後用100 ng/ml GM-CSF(#300-03,PeproTech)及250 ng/ml IL-4(#200-04,PeproTech)將黏附單核細胞刺激5-7天，接著用5 μg/mL來自鼠傷寒沙門氏桿菌(Salmonella typhimurium )之LPS(#437650,Sigma)及50 ng/mL IFN-γ(#285-IF,R&D Systems)再活化2天以誘導樹突狀細胞成熟。Mononuclear cells are collected from human peripheral monocytes by leukocyte infiltration. Then supplemented with 10% FBS and 2 mM L- Glutamic acid amide (all from Invitrogen) of RPMI 1640 medium, at a density of 1 × 10 6 cells of the mononuclear cells were seeded in 96-well plates. After overnight incubation at 37 ° C, adherent cells were retained on the plate. Adherent monocytes were stimulated with 100 ng/ml GM-CSF (#300-03, PeproTech) and 250 ng/ml IL-4 (#200-04, PeproTech) for 5-7 days, followed by 5 μg/mL LPS (#437650, Sigma) from Salmonella typhimurium and 50 ng/mL IFN-γ (#285-IF, R&D Systems) were reactivated for 2 days to induce dendritic cell maturation.

在樹突狀細胞活化後，用補充有100-200 U/mL IL-2(#CYT-209,ProSpec-Tany TechnoGene)及100 ng/mL抗CD3抗體(#555336,PharMingen)、T細胞(每孔2-3×105 個細胞)及IDO化合物之連續稀釋液的完全RPMI 1640置換培養基。培育2天以上後，依照製造商說明書(#1647229,Roche Molecular Biochemicals)、使用比色法細胞增殖ELISA套組、藉由BrdU合併檢定來量測T細胞增殖。在10 μM BrdU標記溶液之存在下將細胞連續培育16-18小時。接著，移除標記培養基，且向細胞中添加每孔200 μL FixDenat且在室溫下培育30分鐘。移除FixDenat溶液且每孔添加100 μL抗BrdU-POD抗體結合物工作溶液。在室溫下進行反應90分鐘。接著移除抗體結合物，且以每孔200 μL洗滌溶液將細胞沖洗三次。最後，每孔添加100 μL受質溶液且在顯色期間使用微盤讀取器(Spectra Max PLUS,Molecular Devices)獲得結果。在多個時點下獲得多個讀數以確保數據在線性範圍內。以常規方式獲取重複實驗之數據，且包括適當對照物。參看：Terness P等人，2002,J.Exp.Med., 196(4)：447-57；及Hwu,P等人，2000,J.Immunol. ,164(7)：3596-9。After activation of dendritic cells, supplemented with 100-200 U/mL IL-2 (#CYT-209, ProSpec-Tany TechnoGene) and 100 ng/mL anti-CD3 antibody (#555336, PharMingen), T cells (per complete RPMI) and serial dilutions of the hole 2-3 × 10 5 cells of IDO compounds 1640 medium was replaced. After 2 days of incubation, T cell proliferation was measured by BrdU combined assay using a colorimetric cell proliferation ELISA kit according to the manufacturer's instructions (#1647229, Roche Molecular Biochemicals). The cells were incubated continuously for 16-18 hours in the presence of a 10 μM BrdU labeling solution. Next, the labeling medium was removed, and 200 μL of FixDenat per well was added to the cells and incubated at room temperature for 30 minutes. The FixDenat solution was removed and 100 μL of anti-BrdU-POD antibody conjugate working solution was added per well. The reaction was carried out at room temperature for 90 minutes. The antibody conjugate was then removed and the cells were washed three times with 200 μL of wash solution per well. Finally, 100 μL of the substrate solution was added to each well and the results were obtained using a microplate reader (Spectra Max PLUS, Molecular Devices) during color development. Multiple readings are taken at multiple time points to ensure that the data is in a linear range. Data from repeated experiments were obtained in a conventional manner and included appropriate controls. See: Tennis P et al, 2002, J. Exp. Med., 196(4): 447-57; and Hwu, P et al, 2000, J. Immunol. , 164(7): 3596-9.

實例D：活體內測試IDO抑制劑之抗腫瘤活性Example D: In vivo testing of anti-tumor activity of IDO inhibitors

可使用經修改之腫瘤同種異體移植物/異種移植物方案測試活體內抗腫瘤功效。舉例而言，在文獻中已描述IDO抑制可與細胞毒素化學療法協同作用於免疫活性小鼠中(Muller,A.J.等人。2005,Nat.Med. 11：312-319)。藉由比較研究性IDO抑制劑在免疫勝任同源小鼠中生長之鼠腫瘤異種移植物模型(例如B16及相關變異體、CT-26、LLC)中之協同作用與在經中和性抗CD4抗體處理之同源小鼠中或在免疫功能不全小鼠(例如nu/nu)中生長之相同腫瘤中所觀測之協同作用，展示此協同作用依賴於T細胞。In vivo anti-tumor efficacy can be tested using a modified tumor allograft/xenograft protocol. For example, IDO inhibition has been described in the literature to be synergistic with cytotoxic chemotherapy in immunocompetent mice (Muller, AJ et al. 2005, Nat. Med. 11: 312-319). Synergistic effect of a neutralizing anti-CD4 in a murine tumor xenograft model (eg, B16 and related variants, CT-26, LLC) grown in immunocompetent homologous mice by comparing research IDO inhibitors The synergistic effect observed in antibody-treated homologous mice or in the same tumors grown in immunocompromised mice (eg, nu/nu) demonstrates that this synergy is dependent on T cells.

免疫勝任小鼠相對於免疫功能不全小鼠中之不同抗腫瘤作用之概念亦可允許以單一藥劑測試研究性IDO抑制劑。舉例而言，LLC腫瘤在其同源宿主品系C57Bl/6中生長良好。然而，若此等小鼠經IDO抑制劑1-MT(相對於安慰劑)處理，則腫瘤之形成明顯延遲，意味著IDO抑制為生長抑制(Friberg,M.等人，2002,Int.J.Cancer 101：151-155)。遵循此邏輯，可檢驗IDO抑制在生長於C57Bl/6免疫勝任小鼠中之LLC異種移植腫瘤模型中之功效且將其與IDO抑制劑對裸鼠或SCID小鼠(或經中和T細胞活性之抗體處理之C57Bl/6小鼠)中之LLC腫瘤生長的影響進行比較。由於視不同腫瘤模型之潛在免疫原性而定，減輕腫瘤介導之IDO之免疫抑制性活性的作用可能會不同，因此可對腫瘤細胞進行基因修飾以增強其潛在免疫原性。舉例而言，GM-CSF表現於B16.F10細胞中可增強其潛在免疫原性(Dranoff,G.等人，1993,Proc.Natl.Acad.Sci.,USA ,90：3539-3543)。同樣，在一些腫瘤模型(例如B16.F10)中，可產生表現免疫刺激性蛋白(諸如GM-CSF)之[多]純系且測試IDO抑制劑在免疫勝任小鼠與免疫功能不全小鼠中抵抗由此等腫瘤細胞形成之腫瘤之生長抑制作用。The concept of immunization of competent mice against different anti-tumor effects in immunocompromised mice may also allow for the testing of research IDO inhibitors with a single agent. For example, LLC tumors grow well in their homologous host line C57Bl/6. However, if these mice were treated with the IDO inhibitor 1-MT (relative to placebo), tumor formation was significantly delayed, implying that IDO inhibition was growth inhibition (Friberg, M. et al., 2002, Int . J. Cancer 101: 151-155). Following this logic, the efficacy of IDO inhibition in LLC xenograft tumor models grown in C57B1/6 immunized mice can be examined and compared with IDO inhibitors in nude mice or SCID mice (or neutralized T cell activity). The effect of LLC tumor growth in antibody-treated C57B1/6 mice was compared. Since the effects of reducing the immunosuppressive activity of tumor-mediated IDO may be different depending on the potential immunogenicity of different tumor models, tumor cells may be genetically modified to enhance their potential immunogenicity. For example, GM-CSF is expressed in B16.F10 cells to enhance its potential immunogenicity (Dranoff, G. et al, 1993, Proc. Natl. Acad. Sci., USA , 90: 3539-3543). Similarly, in some tumor models (eg, B16.F10), [multiple] lines expressing immunostimulatory proteins (such as GM-CSF) can be produced and tested for IDO inhibitors in immune competent mice and immunocompromised mice. This inhibits the growth of tumors formed by tumor cells.

用於評定IDO抑制劑之活體內功效之第三種途徑係使用「預免疫」鼠腫瘤同種異體移植物/異種移植物模型。在此等模型中，使免疫勝任小鼠致敏於一或多種特異性腫瘤抗原，以模擬治療性抗腫瘤疫苗接種。由此將小鼠預致敏，以便當隨後在異種移植物實驗中用鼠腫瘤細胞株(具有與用於免疫之彼等腫瘤抗原類似之腫瘤抗原)激發小鼠時，由免疫系統介導抗腫瘤反應。IDO之表現已展示可減弱抗腫瘤反應且容許異種移植物更迅速生長。重要地是，IDO抑制劑1-MT抑制此模型中之腫瘤生長(Uyttenhove,C.等人，2003,Nat.Med. 9：1269-1274)。此模型因IDO活性容許P815腫瘤生長而尤其吸引人，且IDO之特定抑制因此應為生長抑制。A third approach for assessing the in vivo efficacy of IDO inhibitors is to use a "pre-immunized" murine tumor allograft/xenograft model. In these models, immunized competent mice are sensitized to one or more specific tumor antigens to mimic therapeutic anti-tumor vaccination. The mice are thus pre-sensitized so as to be mediated by the immune system when subsequently challenged with a murine tumor cell line (having a tumor antigen similar to the tumor antigens used for immunization) in a xenograft experiment. Tumor response. The performance of IDO has been shown to attenuate anti-tumor responses and allow xenografts to grow more rapidly. Importantly, the IDO inhibitor 1-MT inhibited tumor growth in this model (Uyttenhove, C. et al, 2003, Nat. Med. 9: 1269-1274). This model is particularly attractive because IDO activity allows P815 tumor growth, and the specific inhibition of IDO should therefore be growth inhibition.

最後，治療性免疫可用於評估IDO抑制劑在活體內之影響。舉例而言，已利用B16-BL6細胞證明，經由靜脈內注射腫瘤細胞、接著用該等腫瘤細胞所表現之經良好表徵之免疫原性肽(例如TRP-2)處理可激發Blk/6小鼠(Ji等人，2005,J.Immunol ,175：1456-63)。重要地是，諸如抗CTL-4抗體之免疫系統調節劑可改善對該等治療性免疫之反應。可在使用或不使用IDO抑制劑之情況下、以類似方式(腫瘤肽免疫)評估IDO抑制劑之影響。依據動物存活期(至發病之時間)或藉由在限定時點對腫瘤轉移至肺及/或其他器官進行量測來評定功效。Finally, therapeutic immunity can be used to assess the effects of IDO inhibitors in vivo. For example, B16-BL6 cells have been demonstrated to stimulate Blk/6 mice by intravenous injection of tumor cells followed by treatment with well characterized immunogenic peptides (eg, TRP-2) expressed by such tumor cells. (Ji et al., 2005, J. Immunol , 175: 1456-63). Importantly, immune system modulators such as anti-CTL-4 antibodies can improve the response to such therapeutic immunity. The effect of the IDO inhibitor can be assessed in a similar manner (tumor peptide immunization) with or without the use of an IDO inhibitor. Efficacy is assessed based on animal survival (to the time of onset) or by measuring tumor metastasis to the lungs and/or other organs at defined time points.

在任何/所有上述模型中，亦可直接及/或間接量測腫瘤反應性免疫細胞之數目及/或活性。用於量測腫瘤反應性免疫細胞之數目及/或活性之方法已充分確立且可使用熟習此項技術者熟知之技術執行(Current Protocols in Immunology，第4卷，Coligan,J.E.等人；Immunotherapy of Cancer ,Human Press,2006,Disis,M.L.及其參考文獻)。理論上，IDO之免疫抑制作用之降低可使腫瘤特異性免疫細胞之數目或反應性增加。此外，IDO抑制當與其他治療劑(例如化學治療劑及/或免疫調節劑(例如抗CTLA4抗體))組合時，可進一步增加腫瘤反應性免疫細胞之數目或反應性。The number and/or activity of tumor-reactive immune cells can also be directly and/or indirectly measured in any/all of the above models. Methods for measuring the number and/or activity of tumor-reactive immune cells are well established and can be performed using techniques well known to those skilled in the art (Current Protocols in Immunology, Vol. 4, Coligan, JE et al; Immunotherapy of Cancer , Human Press, 2006, Disis, ML and references. In theory, a decrease in the immunosuppressive effect of IDO can increase the number or reactivity of tumor-specific immune cells. In addition, IDO inhibition can further increase the number or reactivity of tumor-reactive immune cells when combined with other therapeutic agents, such as chemotherapeutic agents and/or immunomodulators (eg, anti-CTLA4 antibodies).

所有同種異體移植物/異種移植物實驗可使用標準腫瘤技術進行(回顧於Corbett等人之Cancer Drug Discovery and Development：Anticancer Drug Development Guide：Preclinical Screening,Clinical Trials,and Approval ，第2版。Teicher,B.A.and Andrews,P.A.,Gumana Press Inc.：Totowa,NJ,2004中)。可使用熟習此項技術者熟知之技術將基因(例如IDO、GM-CSF)選殖及引入腫瘤細胞株中(回顧於Sambrook,J.及Russel,D.,Molecular Cloning：A laboratory Manual(第3版) ，Cold Spring Harbor Laboratory Press：Cold Spring Harbor,NY,2001中)。All allograft/xenograft experiments can be performed using standard tumor techniques (reviewed in Corbett et al., Cancer Drug Discovery and Development: Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval , 2nd ed. Teicher, BAand Andrews, PA, Gumana Press Inc.: Totowa, NJ, 2004). Genes (eg, IDO, GM-CSF) can be cloned and introduced into tumor cell lines using techniques well known to those skilled in the art (reviewed in Sambrook, J. and Russel, D., Molecular Cloning: A laboratory Manual (3rd) Edition) , Cold Spring Harbor Laboratory Press: Cold Spring Harbor, NY, 2001).

實例E：在人類免疫缺乏病毒-1(HIV-1)腦炎模型中對IDOExample E: IDO in a model of human immunodeficiency virus-1 (HIV-1) encephalitis 抑制劑進行活體內測試Inhibitor for in vivo testing 1.細胞分離及病毒感染1. Cell separation and viral infection

可藉由逆流離心淘析來自HIV-1、HIV-2及B型肝炎血清反應陰性之供體之白細胞清除包來獲得單核細胞及PBL。使用鐵氟龍(Teflon)燒瓶、在補充有10%熱滅活混合人類血清、1%麩醯胺酸、50 μg/mL慶大黴素(gentamicin)、10 μg/mL環丙沙星(ciprofloxacin)(Sigma)及1000 U/mL高度純化重組人類巨噬細胞群落刺激因子之杜貝克氏改良伊格爾氏培養基(Dulbecco's Modified Eagle's Medium,DMEM,Sigma-Aldrich)中、在懸浮液培養物中培養單核細胞。培養7天後，以0.01之感染倍率用HIV-1ADA 感染MDM。Mononuclear cells and PBL can be obtained by countercurrent centrifugation of leukocyte clearance packets from HIV-1, HIV-2 and hepatitis B seropositive donors. Use a Teflon flask supplemented with 10% heat inactivated mixed human serum, 1% branic acid, 50 μg/mL gentamicin, 10 μg/mL ciprofloxacin (Sigma) and 1000 U/mL highly purified recombinant human macrophage colony stimulating factor in Dulbecco's Modified Eagle's Medium (DMEM, Sigma-Aldrich), cultured in suspension culture Monocytes. After 7 days of culture, MDM was infected with HIV-1 ADA at an infection rate of 0.01.

2. Hu-PBL-NOD/SCID HIVE小鼠2. Hu-PBL-NOD/SCID HIVE mice

可購買四週齡之雄性NOD/C.B-17 SCID小鼠(Jackson Laboratory)。在無病原條件下將動物供養在無菌微隔離籠中。將所有動物在PBL移植之前3天腹膜內注射大鼠抗CD122(每隻小鼠0.25 mg)且在PBL注射(每隻小鼠20×106 個細胞)之前1天及之後3天注射兔脫唾液酸-GM1抗體兩次(每隻小鼠0.2 mg)(Wako)。在PBL重構後8天，顱內(i.c.)注射感染HIV-1ADA 之MDM(3×105 個細胞，10 μL)，產生hu-PBL-NOD/SCID HIVE小鼠。在顱內注射感染HIV-1之MDM後，立即將對照物(媒劑)或化合物丸粒(14或28天緩慢釋放，Innovative Research)皮下(s.c)植入hu-PBL-NOD/SCID HIVE小鼠內。初始實驗設計成證明病毒特異性CTL誘導於經IDO化合物處理之hu PBL-NOD/SCID HIVE動物中。此係藉由自腦組織切除之MDM之四聚體染色及神經病理學分析來證明。隨後，實驗設計成分析人類淋巴細胞重構、體液免疫反應及神經病理學改變。在此等實驗中，在顱內注射人類MDM後第7天將動物放血且在第14天及第21天處死。收集於含有EDTA之試管中的血液用於流式細胞計數且血漿用於使用ELISA(Beckman CoulterTM )來偵測HIV-1 p24。根據製造商說明書(Cambridge Biotech HIV-1西方墨點套組，Calypte Biomedical)藉由西方墨點測試來偵測HIV-1特異性抗體。在經對照物及化合物處理之動物中偵測到類似量之病毒特異性抗體。可使用三個不同之人類白血球供體進行總計三個獨立實驗。Four-year-old male NOD/CB-17 SCID mice (Jackson Laboratory) can be purchased. Animals were maintained in sterile micro-isolation cages under pathogen free conditions. All animals before PBL transplantation, rats were injected intraperitoneally 3 days of anti-CD122 (0.25 mg per mouse) and before PBL injection (20 × 10 6 per mouse cells) 1 day and 3 days after injection Tutuo The sialic acid-GM1 antibody was twice (0.2 mg per mouse) (Wako). Eight days after PBL reconstitution, MDM (3 x 10 5 cells, 10 μL) infected with HIV-1 ADA was injected intracranially (ic) to produce hu-PBL-NOD/SCID HIVE mice. Immediately after intracranial injection of MDM infected with HIV-1, the control (vehicle) or compound pellet (14 or 28 days of slow release, Innovative Research) was subcutaneously (sc) implanted into hu-PBL-NOD/SCID HIVE Inside the mouse. Initial experiments were designed to demonstrate that virus-specific CTL was induced in hu PBL-NOD/SCID HIVE animals treated with IDO compounds. This was demonstrated by tetramer staining and neuropathological analysis of MDM excised from brain tissue. Subsequently, the experiment was designed to analyze human lymphocyte remodeling, humoral immune response, and neuropathological changes. In these experiments, animals were bled on day 7 after intracranial injection of human MDM and sacrificed on days 14 and 21. Collected in tubes containing EDTA in the blood for flow cytometry and plasma using ELISA (Beckman Coulter TM) to detect HIV-1 p24. HIV-1 specific antibodies were detected by Western blot testing according to the manufacturer's instructions (Cambridge Biotech HIV-1 Western Ink Set, Calypte Biomedical). A similar amount of virus-specific antibody was detected in the control and compound treated animals. A total of three independent experiments can be performed using three different human white blood cell donors.

3.對hu PBL-NOD/SCID HIVE小鼠中之外周血液及脾臟之流式細胞分析(FACScan) 3. Flow cytometric analysis of peripheral blood and spleen in hu PBL-NOD/SCID HIVE mice (FACScan)

在顱內注射人類MDM後第1-3週可對外周血液進行雙色FACS分析且在第2週及第3週可對脾細胞進行雙色FACS分析。在4℃下用螢光染料結合之抗人類CD4、CD8、CD56、CD3、IFN-γ的單株Abs(mAbs)(eBioscience)培育細胞30分鐘。為評估細胞免疫反應，將IFN-γ細胞內染色與抗人類CD8及FITC結合之抗小鼠CD45組合執行以排除鼠細胞。為測定Ag特異性CTL，將植物血凝素/介白素-2(PHA/IL-2)刺激之脾細胞用針對HIV-1gag (p17(aa77-85)SLYNTVATL，SL-9)及HIV-1pol [(aa476-485)ILKEPVHGV，IL-9]之別藻藍蛋白結合四聚體染色。依循NIH/美國團家過敏與傳染病研究院(National Institute of Allergy and Infections Disease)、National Tetramer Core Facilities之建議將細胞染色。使用CellQuest軟體(Becton Dickinson Immunocytometry System)、以FACS CaliburTM 來分析數據。Two-color FACS analysis of peripheral blood was performed at 1-3 weeks after intracranial injection of human MDM and spleen cells were subjected to two-color FACS analysis at weeks 2 and 3. The cells were incubated with fluorescent dye-conjugated monoclonal Abs (mAbs) (eBioscience) against human CD4, CD8, CD56, CD3, IFN-γ for 30 minutes at 4 °C. To assess cellular immune responses, IFN-[gamma] intracellular staining was performed in combination with anti-human CD8 and FITC-conjugated anti-mouse CD45 to exclude murine cells. For the determination of Ag-specific CTL, phytohemagglutinin/interleukin-2 (PHA/IL-2)-stimulated spleen cells were used against HIV-1 gag (p17(aa77-85)SLYNTVATL, SL-9) and HIV -1 pol [(aa476-485) ILKEPVHGV, IL-9] is a phycocyanin-binding tetramer stain. Cells were stained following the recommendations of the NIH/National Institute of Allergy and Infections Disease, National Tetramer Core Facilities. Using CellQuest software (Becton Dickinson Immunocytometry System), in order to analyze the data FACS Calibur TM.

4.組織病理學及影像分析4. Histopathology and image analysis

在顱內注射MDM後第14天及第21天收集腦組織，將其固定於經4%磷酸鹽緩衝之三聚甲醛中且嵌埋於石蠟中或在-80℃下冷凍以備後用。自嵌埋塊切割冠狀切片以鑑別注射部位。對於各小鼠而言，自人類MDM注射部位切割30-100個(5 μm厚)連續切片且分析3-7個載片(相隔10個切片)。用二甲苯將腦切片脫去石蠟且水合於梯度醇中。免疫組織化學染色係依循使用抗原修復之基本間接方案，藉由在0.01 mol/L檸檬酸鹽緩衝液中加熱至95℃歷時30分鐘來達成抗原修復。為鑑別小鼠腦中之人類細胞，使用鑑別所有人類白血球之波形絲蛋白(vimentin)：mAb(1：50，純系3B4，Dako Corporation)。分別用CD68(1：50稀釋度，純系KP 1)及CD8(1：50稀釋度，純系144B)抗體來偵測人類MDM及CD8+ 淋巴細胞。用mAb：HIV-1 p24(1：10，純系Kal-1，均來自Dako)標記感染病毒之細胞。用Iba-1抗體(1：500，Wako)偵測反應性鼠微小膠質細胞。用獲自Department of Cell Pharmacology,Central Research Institute,Graduate School of Medicine,Hokkaido University,Sapporo,Japan之Abs顯現人類IDO(huIDO)之表現。初級抗體係用適當生物素標記之二次抗體偵測且用抗生物素蛋白-生物素複合物(Vectastain Elite ABC套組，Vector Laboratories)及辣根過氧化酶(HRP)偶合之葡聚糖聚合物(EnVision,Dako Corporation)顯現。將經免疫染色之切片用邁爾氏蘇木精(Mayer's hematoxylin)對比染色。其中初級抗體缺失或合併不相關IgG同種型之切片用作對照物。兩個獨立觀測者以盲法對各小鼠之各切片中之CD8+ 淋巴細胞、CD68+ MDM及HIV-1 p24+ 細胞之數目計數。用Nikon Eclipse 800顯微鏡(Nikon Instruments Inc)進行光顯微檢驗。如上所述，藉由電腦輔助影像分析(Image-ProPlus,Media Cybernetics)對Iba1進行半定量分析(免疫染色所佔面積百分比)。Brain tissue was collected on days 14 and 21 after intracranial injection of MDM, fixed in 4% phosphate buffered paraformaldehyde and embedded in paraffin or frozen at -80 °C for later use. Coronal sections were cut from the embedded block to identify the injection site. For each mouse, 30-100 (5 μm thick) serial sections were cut from the human MDM injection site and 3-7 slides were analyzed (10 sections apart). The brain sections were deparaffinized with xylene and hydrated in a gradient alcohol. Immunohistochemical staining was followed by a basic indirect protocol using antigen retrieval by antigen heating in a 0.01 mol/L citrate buffer to 95 °C for 30 minutes. To identify human cells in the mouse brain, vimentin was identified using all human leukocytes: mAb (1:50, pure line 3B4, Dako Corporation). Human MDM and CD8 + lymphocytes were detected by CD68 (1:50 dilution, pure KP 1) and CD8 (1:50 dilution, pure 144B) antibodies, respectively. The virus-infected cells were labeled with mAb: HIV-1 p24 (1:10, pure Kal-1, all from Dako). Reactive murine microglia were detected with an Iba-1 antibody (1:500, Wako). The performance of human IDO (huIDO) was visualized with Abs obtained from the Department of Cell Pharmacology, Central Research Institute, Graduate School of Medicine, Hokkaido University, Sapporo, Japan. The primary anti-system is detected with a suitable biotin-labeled secondary antibody and polymerized with avidin-biotin complex (Vectastain Elite ABC kit, Vector Laboratories) and horseradish peroxidase (HRP). (EnVision, Dako Corporation) appeared. Immunostained sections were contrast-stained with Mayer's hematoxylin. Sections in which primary antibodies were deleted or combined with unrelated IgG isotypes were used as controls. Two independent observers counted the number of CD8 + lymphocytes, CD68 + MDM, and HIV-1 p24 + cells in each section of each mouse in a blinded manner. Light microscopy was performed using a Nikon Eclipse 800 microscope (Nikon Instruments Inc). As described above, with computer-aided image analysis (Image-Pro Plus, Media Cybernetics) Semi-quantitative analysis of Iba1 (% of area occupied by immunostaining).

5.統計分析5. Statistical analysis

可使用Prism(Graph Pad)、以用於比較之學生t -檢驗法及ANOVA分析數據。P 值小於0.05視為顯著。Data can be analyzed using Prism (Graph Pad) for Student's t -test and ANOVA for comparison. A P value of less than 0.05 is considered significant.

6.參考文獻6. References

Poluektova LY,Munn DH,Persidsky Y,and Gendelman HE(2002).Generation of cytotoxic T cells against virus-infected human brain macrophages in a murine model of HIV-1 encephalitis.J.Immunol .168(8)：3941-9。Poluektova LY, Munn DH, Persidsky Y, and Gendelman HE (2002). Generation of cytotoxic T cells against virus-infected human brain macrophages in a murine model of HIV-1 encephalitis. J.Immunol .168(8):3941-9 .

除本文所述之彼等內容外，熟習此項技術者經由以上說明亦將顯而易見本發明之各種修改。該等修改亦希望屬於隨附申請專利範圍之範疇內。本申請案所引用之各參考文獻(包括所有專利、專利申請案及公開案)之全文均以引用的方式併入本文中。Various modifications of the invention will become apparent to those skilled in the <RTIgt; Such modifications are also intended to fall within the scope of the accompanying patent application. The entire contents of each of the references (including all patents, patent applications, and publications) cited in this application are hereby incorporated by reference.

圖1顯示實例1中所製備之本發明化合物的XRPD圖案特徵；圖2顯示實例1中所製備之本發明化合物的DSC熱分析圖特徵；及圖3顯示實例1中所製備之本發明化合物的TGA數據特徵。1 shows the XRPD pattern characteristics of the compound of the present invention prepared in Example 1; FIG. 2 shows the DSC thermogram characteristics of the compound of the present invention prepared in Example 1; and FIG. 3 shows the compound of the present invention prepared in Example 1. TGA data characteristics.

無元件符號說明No component symbol description

Claims (140)

一種式I化合物： 或其醫藥學上可接受之鹽，其中：R1 為NH2 或CH3 ；R2 為Cl、Br、CF3 、CH3 或CN；R3 為H或F；及n為1或2。A compound of formula I: Or a pharmaceutically acceptable salt thereof, wherein: R 1 is 2 NH2 or CH 3; R 2 is Cl, Br, CF 3, CH 3 or CN; R 3 is H or F; and n is 1 or 2. 如請求項1之化合物，或其醫藥學上可接受之鹽，其中R1 為NH2 。The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is NH 2 . 如請求項1之化合物，或其醫藥學上可接受之鹽，其中R1 為CH3 。The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is CH 3 . 如請求項1至3中任一項之化合物，或其醫藥學上可接受之鹽，其中R2 為Cl。The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 2 is Cl. 如請求項1至3中任一項之化合物，或其醫藥學上可接受之鹽，其中R2 為Br。The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 2 is Br. 如請求項1至3中任一項之化合物，或其醫藥學上可接受之鹽，其中R2 為CF3 。The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 2 is CF 3 . 如請求項1至3中任一項之化合物，或其醫藥學上可接受之鹽，其中R2 為CH3 。The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 2 is CH 3 . 如請求項1至3中任一項之化合物，或其醫藥學上可接受 之鹽，其中R2 為CN。The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 2 is CN. 如請求項1至3中任一項之化合物，或其醫藥學上可接受之鹽，其中R3 為H。The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 3 is H. 如請求項1至3中任一項之化合物，或其醫藥學上可接受之鹽，其中R3 為F。The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 3 is F. 如請求項1至3中任一項之化合物，或其醫藥學上可接受之鹽，其中n為1。 The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein n is 1. 如請求項1至3中任一項之化合物，或其醫藥學上可接受之鹽，其中n為2。 The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein n is 2. 如請求項1之化合物，其係選自：4-({2-[(胺基磺醯基)胺基]乙基}胺基)-N -(3-溴-4-氟苯基)-N' -羥基-1,2,5-二唑-3-甲醯亞胺醯胺；N -(3-溴-4-氟苯基)-N' -羥基-4-({2-[(甲基磺醯基)胺基]乙基}胺基)-1,2,5-二唑-3-甲醯亞胺醯胺；4-({3-[(胺基磺醯基)胺基]丙基}胺基)-N -(3-溴-4-氟苯基)-N' -羥基-1,2,5-二唑-3-甲醯亞胺醯胺；N -(3-溴-4-氟苯基)-N' -羥基-4-({3-[(甲基磺醯基)胺基]丙基}胺基)-1,2,5-二唑-3-甲醯亞胺醯胺；4-({2-[(胺基磺醯基)胺基]乙基}胺基)-N -(3-氯-4-氟苯基)-N' -羥基-1,2,5-二唑-3-甲醯亞胺醯胺；N -(3-氯-4-氟苯基)-N' -羥基-4-({2-[(甲基磺醯基)胺基]乙基}胺基)-1,2,5-二唑-3-甲醯亞胺醯胺；4-({3-[(胺基磺醯基)胺基]丙基}胺基)-N -(3-氯-4-氟苯基)-N' -羥基-1,2,5-二唑-3-甲醯亞胺醯胺；N -(3-氯-4-氟苯基)-N' -羥基-4-({3-[(甲基磺醯基)胺基]丙基}胺基)-1,2,5-二唑-3-甲醯亞胺醯胺；4-({2-[(胺基磺醯基)胺基]乙基}胺基)-N -[4-氟-3-(三氟甲基)苯基]-N' -羥基-1,2,5-二唑-3-甲醯亞胺醯胺；N -[4-氟-3-(三氟甲基)苯基]-N' -羥基-4-({2-[(甲基磺醯基)胺基]乙基}-胺基)-1,2,5-二唑-3-甲醯亞胺醯胺；4-({3-[(胺基磺醯基)胺基]丙基}胺基)-N -[4-氟-3-(三氟甲基)苯基]-N' -羥基-1,2,5-二唑-3-甲醯亞胺醯胺；N -[4-氟-3-(三氟甲基)苯基]-N' -羥基-4-({3-[(甲基磺醯基)胺基]丙基}-胺基)-1,2,5-二唑-3-甲醯亞胺醯胺；4-({2-[(胺基磺醯基)胺基]乙基}胺基)-N' -羥基-N -[3-(三氟甲基)苯基]-1,2,5-二唑-3-甲醯亞胺醯胺；N' -羥基-4-({2-[(甲基磺醯基)胺基]乙基}胺基)-N -[3-(三氟甲基)苯基]-1,2,5-二唑-3-甲醯亞胺醯胺；4-({3-[(胺基磺醯基)胺基]丙基}胺基)-N' -羥基-N -[3-(三氟甲基)苯基]-1,2,5-二唑-3-甲醯亞胺醯胺；N' -羥基-4-({3-[(甲基磺醯基)胺基]丙基}胺基)-N -[3-(三氟甲基)苯基]-1,2,5-二唑-3-甲醯亞胺醯胺；N -(4-氟-3-甲基苯基)-N '-羥基-4-({2-[(甲基磺醯基)胺基]乙基}胺基)-1,2,5-二唑-3-甲醯亞胺醯胺；4-({2-[(胺基磺醯基)胺基]乙基}胺基)-N -(3-氰基-4-氟苯基)-N' -羥基-1,2,5-二唑-3-甲醯亞胺醯胺；及N -(3-氰基-4-氟苯基)-N' -羥基-4-({2-[(甲基磺醯基)胺基]乙基}胺基)-1,2,5-二唑-3-甲醯亞胺醯胺； 或其醫藥學上可接受之鹽。The compound according to item 1 of the request, which is selected from: 4 - ({2 - [(sulfo amino acyl) amino] ethyl} amino) - N - (3- bromo-4-fluorophenyl) - N' -hydroxy-1,2,5- Oxadiazol-3-amine (PEI) acyl; N - (3- bromo-4-fluorophenyl) - N '- hydroxy-4 - ({2 - [(acyl sulfo methyl) amino] ethyl }amine)-1,2,5- Oxadiazol-3-amine (PEI) acyl; 4 - ({3 - [(acyl group sulfo) amino] propyl} amino) - N - (3- bromo-4-fluorophenyl) - N' -hydroxy-1,2,5- Oxadiazol-3-amine (PEI) acyl; N - (3- bromo-4-fluorophenyl) - N '- hydroxy-4 - ({3 - [(acyl sulfo methyl) amino] propyl }amine)-1,2,5- Oxadiazol-3-amine (PEI) acyl; 4 - ({2 - [(sulfo amino acyl) amino] ethyl} amino) - N - (3- chloro-4-fluorophenyl) - N' -hydroxy-1,2,5- Oxadiazol-3-amine (PEI) acyl; N - (3- chloro-4-fluorophenyl) - N '- hydroxy-4 - ({2 - [(acyl sulfo methyl) amino] ethyl }amine)-1,2,5- Oxadiazol-3-amine (PEI) acyl; 4 - ({3 - [(acyl group sulfo) amino] propyl} amino) - N - (3- chloro-4-fluorophenyl) - N' -hydroxy-1,2,5- Oxadiazol-3-amine (PEI) acyl; N - (3- chloro-4-fluorophenyl) - N '- hydroxy-4 - ({3 - [(acyl sulfo methyl) amino] propyl }amine)-1,2,5- Oxadiazol-3-amine (PEI) acyl; 4 - ({2 - [(sulfo amino acyl) amino] ethyl} amino) - N - [4- fluoro-3- (trifluoromethyl ) phenyl] - N '- hydroxy-1,2,5 Diazole-3-carboximine amide; N- [4-fluoro-3-(trifluoromethyl)phenyl] -N' -hydroxy-4-({2-[(methylsulfonyl)) Amino]ethyl}-amino)-1,2,5- Oxadiazol-3-amine (PEI) acyl; 4 - ({3 - [(acyl group sulfo) amino] propyl} amino) - N - [4- fluoro-3- (trifluoromethyl ) phenyl] - N '- hydroxy-1,2,5 Oxazole-3-carboximine amide; N- [4-fluoro-3-(trifluoromethyl)phenyl] -N' -hydroxy-4-({3-[(methylsulfonyl)) Amino]propyl}-amino)-1,2,5- Oxadiazol-3-amine (PEI) acyl; 4 - ({2 - [(sulfo amino acyl) amino] ethyl} amino) - N '- hydroxy - N - [3- (trifluoromethanesulfonyl Phenyl]-1,2,5- Oxadiazol-3-amine (PEI) acyl; N '- hydroxy-4 - ({2 - [(acyl sulfo methyl) amino] ethyl} amino) - N - [3- (trifluoromethanesulfonyl Phenyl]-1,2,5- Oxadiazol-3-amine (PEI) acyl; 4 - ({3 - [(acyl group sulfo) amino] propyl} amino) - N '- hydroxy - N - [3- (trifluoromethanesulfonyl Phenyl]-1,2,5- Oxadiazol-3-amine (PEI) acyl; N '- hydroxy-4 - ({3 - [(acyl sulfo methyl) amino] propyl} amino) - N - [3- (trifluoromethanesulfonyl Phenyl]-1,2,5- Diazol-3-carboximine amide; N- (4-fluoro-3-methylphenyl) -N '-hydroxy-4-({2-[(methylsulfonyl)amino]B Amino group-1,2,5- Oxadiazol-3-amine (PEI) acyl; 4 - ({2 - [(sulfo amino acyl) amino] ethyl} amino) - N - (3- cyano-4-fluorophenyl) - N' -hydroxy-1,2,5- Oxadiazol-3-amine (PEI) acyl; and N - (3- cyano-4-fluorophenyl) - N '- hydroxy-4 - ({2 - [(meth sulfo acyl) amino] Ethyl}amino)-1,2,5- A oxazol-3-carboxamide amide; or a pharmaceutically acceptable salt thereof. 一種化合物，其為4-({2-[(胺基磺醯基)胺基]乙基}胺基)-N -(3-溴-4-氟苯基)-N' -羥基-1,2,5-二唑-3-甲醯亞胺醯胺，或其醫藥學上可接受之鹽。A compound which is 4 - ({2 - [(sulfo amino acyl) amino] ethyl} amino) - N - (3- bromo-4-fluorophenyl) - N '- hydroxy-1, 2,5- A oxazol-3-carboxamide, or a pharmaceutically acceptable salt thereof. 一種化合物，其為4-({2-[(胺基磺醯基)胺基]乙基}胺基)-N -(3-溴-4-氟苯基)-N' -羥基-1,2,5-二唑-3-甲醯亞胺醯胺。A compound which is 4 - ({2 - [(sulfo amino acyl) amino] ethyl} amino) - N - (3- bromo-4-fluorophenyl) - N '- hydroxy-1, 2,5- Diazole-3-carboximine amide. 如請求項15之化合物，其為固體形式且為結晶體。 The compound of claim 15 which is in solid form and is crystalline. 如請求項15之化合物，其為固體形式，包含少於2%水。 The compound of claim 15 which is in solid form and comprises less than 2% water. 如請求項15之化合物，其為固體形式，具有162℃±3℃至166℃±3℃之熔點。 The compound of claim 15 which is in solid form having a melting point of from 162 ° C ± 3 ° C to 166 ° C ± 3 ° C. 如請求項15之化合物，其為固體形式，具有如圖2所示之DSC熱分析圖(thermogram)，其中該DSC熱分析圖之溫度範圍之變異為±3℃。 The compound of claim 15, which is in solid form, has a DSC thermogram as shown in Figure 2, wherein the temperature range of the DSC thermogram is a variation of ± 3 °C. 如請求項15之化合物，其為固體形式，具有以2θ±0.2°表示，至少一個選自18.4°、18.9°、21.8°、23.9°、29.2°及38.7°之XRPD峰。 The compound of claim 15 which is in solid form having an XRPD peak selected from 2θ ± 0.2° and at least one selected from the group consisting of 18.4°, 18.9°, 21.8°, 23.9°, 29.2° and 38.7°. 如請求項15之化合物，其為固體形式，具有以2θ±0.2°表示，至少兩個選自18.4°、18.9°、21.8°、23.9°、29.2°及38.7°之XRPD峰。 The compound of claim 15 which is in solid form having an XRPD peak selected from 2θ ± 0.2° and at least two selected from the group consisting of 18.4°, 18.9°, 21.8°, 23.9°, 29.2° and 38.7°. 如請求項15之化合物，其為固體形式，具有以2θ±0.2°表示，至少三個選自18.4°、18.9°、21.8°、23.9°、29.2°及38.7°之XRPD峰。 The compound of claim 15 which is in solid form having an XRPD peak selected from 2θ ± 0.2° and at least three selected from the group consisting of 18.4°, 18.9°, 21.8°, 23.9°, 29.2° and 38.7°. 如請求項15之化合物，其為固體形式，具有如圖1所示 之XRPD圖，其中該XRPD圖之峰值，以2θ表示，具有±0.2°之變異。 The compound of claim 15 which is in solid form and has the structure shown in Figure 1. The XRPD pattern, wherein the peak of the XRPD pattern, expressed as 2θ, has a variation of ±0.2°. 一種式F28之化合物 或其醫藥學上可接受之鹽，其中：R4 為F、Cl、Br或I；且n為1或2。a compound of formula F28 Or a pharmaceutically acceptable salt thereof, wherein: R 4 is F, Cl, Br or I; and n is 1 or 2. 一種化合物，其為4-({2-[(胺基磺醯基)胺基]乙基}胺基)-N -[(4-溴-2-呋喃基)甲基]-N' -羥基-1,2,5-二唑-3-甲醯亞胺醯胺，或其醫藥學上可接受之鹽。A compound which is 4-({2-[(aminosulfonyl)amino]ethyl}amino) -N -[(4-bromo-2-furyl)methyl] -N' -hydroxy -1,2,5- A oxazol-3-carboxamide, or a pharmaceutically acceptable salt thereof. 一種化合物，其為4-({2-[(胺基磺醯基)胺基]乙基}胺基)-N -[(4-氯-2-呋喃基)甲基]-N' -羥基-1,2,5-二唑-3-甲醯亞胺醯胺，或其醫藥學上可接受之鹽。A compound which is 4-({2-[(aminosulfonyl)amino]ethyl}amino) -N -[(4-chloro-2-furanyl)methyl] -N' -hydroxy -1,2,5- A oxazol-3-carboxamide, or a pharmaceutically acceptable salt thereof. 一種組合物，其包含如請求項1至15及24至26中任一項之化合物或其醫藥學上可接受之鹽，及至少一種醫藥學上可接受之載劑。 A composition comprising a compound according to any one of claims 1 to 15 and 24 to 26, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. 一種如請求項1至15及24至26中任一項之化合物或其醫藥學上可接受之鹽之用途，其係用以製備用於抑制吲哚胺2,3-雙加氧酶活性之藥物。 A use of a compound according to any one of claims 1 to 15 and 24 to 26, or a pharmaceutically acceptable salt thereof, for the preparation of a guanamine 2,3-dioxygenase activity drug. 一種如請求項1至15及24至26中任一項之化合物或其醫藥學上可接受之鹽的用途，係用於製造供抑制患者之免疫抑制之藥物。 A use of a compound according to any one of claims 1 to 15 and 24 to 26, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting immunosuppression in a patient. 一種如請求項1至15及24至26中任一項之化合物或其醫藥學上可接受之鹽的用途，係用於製造供治療患者癌症、病毒感染、抑鬱症、神經退化性病症、創傷、年齡相關性白內障、器官移植排斥反應或自體免疫疾病之藥物。 Use of a compound according to any one of claims 1 to 15 and 24 to 26, or a pharmaceutically acceptable salt thereof, for the manufacture of a cancer, viral infection, depression, neurodegenerative disorder, trauma , age-related cataracts, organ transplant rejection or autoimmune diseases. 如請求項30之用途，其中該癌症選自結腸癌、胰腺癌、乳癌、***癌、肺癌、腦癌、卵巢癌、子宮頸癌、睪丸癌、腎癌、頭頸癌、淋巴瘤及白血病。 The use of claim 30, wherein the cancer is selected from the group consisting of colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, renal cancer, head and neck cancer, lymphoma, and leukemia. 如請求項30之用途，其中該藥物與下列組合使用：抗癌疫苗、抗CTLA-4抗體、抗PD-1抗體、抗病毒劑、化學治療劑、免疫抑制劑、輻射、抗腫瘤疫苗、抗病毒疫苗、細胞因子(cytokine)療法或酪胺酸激酶抑制劑。 The use of claim 30, wherein the medicament is used in combination with an anticancer vaccine, an anti-CTLA-4 antibody, an anti-PD-1 antibody, an antiviral agent, a chemotherapeutic agent, an immunosuppressant, a radiation, an antitumor vaccine, and an antibiotic Viral vaccine, cytokine therapy or tyrosine kinase inhibitor. 如請求項32之用途，其中該細胞因子療法包含IL-2。 The use of claim 32, wherein the cytokine therapy comprises IL-2. 如請求項32之用途，其中該化學治療劑為細胞毒性劑。 The use of claim 32, wherein the chemotherapeutic agent is a cytotoxic agent. 一種如請求項1至15及24至26中任一項之化合物或其醫藥學上可接受之鹽的用途，係用於製造供治療患者之黑素瘤之藥物。 A use of a compound according to any one of claims 1 to 15 and 24 to 26, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating melanoma in a patient. 如請求項35之用途，其中該藥物與下列組合使用：化學治療劑、抗CTLA-4抗體、抗PD-1抗體、輻射、抗腫瘤疫苗或細胞因子療法。 The use of claim 35, wherein the medicament is used in combination with a chemotherapeutic agent, an anti-CTLA-4 antibody, an anti-PD-1 antibody, radiation, an anti-tumor vaccine or a cytokine therapy. 一種製備式F15化合物或其鹽之方法： 其中R2 為Cl、Br、CF3 、CH3 或CN；R3 為H或F；n為1或2，該方法包含：a)使式F13化合物： 或其鹽，其中Pg1 為胺基保護基，與胺基去保護劑反應以產生式F14化合物： 或其鹽；及b)使該式F14化合物與鹼反應以產生該式F15化合物。A method for preparing a compound of the formula F15 or a salt thereof: Wherein R 2 is Cl, Br, CF 3 , CH 3 or CN; R 3 is H or F; n is 1 or 2, and the process comprises: a) bringing a compound of formula F13: Or a salt thereof, wherein Pg 1 is an amine protecting group, is reacted with an amine deprotecting agent to produce a compound of formula F14: Or a salt thereof; and b) reacting the compound of formula F14 with a base to produce the compound of formula F15. 如請求項37之方法，其中R2 為Br，R3 為F，n為1。The method of claim 37, wherein R 2 is Br, R 3 is F, and n is 1. 如請求項37之方法，其中R2 為Br，R3 為F，n為2。The method of claim 37, wherein R 2 is Br, R 3 is F, and n is 2. 如請求項37之方法，其中R2 為Cl，R3 為F，n為1。The method of claim 37, wherein R 2 is Cl, R 3 is F, and n is 1. 如請求項37之方法，其中R2 為Cl，R3 為F，n為2。The method of claim 37, wherein R 2 is Cl, R 3 is F, and n is 2. 如請求項37之方法，其中R2 為CF3 ，R3 為F，n為1。The method of claim 37, wherein R 2 is CF 3 , R 3 is F, and n is 1. 如請求項37之方法，其中R2 為CF3 ，R3 為F，n為2。The method of claim 37, wherein R 2 is CF 3 , R 3 is F, and n is 2. 如請求項37之方法，其中R2 為CF3 ，R3 為H，n為1。The method of claim 37, wherein R 2 is CF 3 , R 3 is H, and n is 1. 如請求項37之方法，其中R2 為CF3 ，R3 為H，n為2。The method of claim 37, wherein R 2 is CF 3 , R 3 is H, and n is 2. 如請求項37之方法，其中R2 為CN，R3 為F，n為1。The method of claim 37, wherein R 2 is CN, R 3 is F, and n is 1. 如請求項37之方法，其中該Pg1 為乙氧羰基、第三丁氧羰基(Boc)、苯甲氧羰基(Cbz)或9-茀基甲氧羰基(Fmoc)。The method of claim 37, wherein the Pg 1 is ethoxycarbonyl, third butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or 9-fluorenylmethoxycarbonyl (Fmoc). 如請求項47之方法，其中該烷氧羰基為第三丁氧羰基。 The method of claim 47, wherein the alkoxycarbonyl group is a third butoxycarbonyl group. 如請求項37之方法，其中該胺基去保護劑為三氟乙酸。 The method of claim 37, wherein the amine deprotecting agent is trifluoroacetic acid. 如請求項37之方法，其中該胺基去保護劑為鹽酸。 The method of claim 37, wherein the amine deprotecting agent is hydrochloric acid. 如請求項50之方法，其中該反應係在包含二烷之溶劑中進行。The method of claim 50, wherein the reaction system comprises two It is carried out in a solvent of an alkane. 如請求項50或51之方法，其中該反應係在異丙醇中進行。 The method of claim 50 or 51, wherein the reaction is carried out in isopropanol. 如請求項37之方法，其中該鹼包含鹼金屬氫氧化物。 The method of claim 37, wherein the base comprises an alkali metal hydroxide. 如請求項37之方法，其中該鹼為氫氧化鈉。 The method of claim 37, wherein the base is sodium hydroxide. 如請求項37之方法，其中該式F13化合物如下獲得：以Pg1 -NH-磺醯氯處理式F12化合物： 或其鹽，隨後以有機鹼處理以產生該式F13化合物。The method of claim 37, wherein the compound of formula F13 is obtained by treating a compound of formula F12 with Pg 1 -NH-sulfonyl chloride: Or a salt thereof, followed by treatment with an organic base to produce the compound of formula F13. 如請求項55之方法，其中該Pg1 包含乙氧羰基、第三丁氧 羰基(Boc)、苯甲氧羰基(Cbz)或9-茀基甲氧羰基(Fmoc)。The method of claim 55, wherein the Pg 1 comprises an ethoxycarbonyl group, a third butoxycarbonyl (Boc), a benzyloxycarbonyl (Cbz) or a 9-fluorenylmethoxycarbonyl group (Fmoc). 如請求項56之方法，其中該烷氧羰基為第三丁氧羰基。 The method of claim 56, wherein the alkoxycarbonyl group is a third butoxycarbonyl group. 如請求項55之方法，其中該處理係在溶劑中進行。 The method of claim 55, wherein the treating is carried out in a solvent. 如請求項55之方法，其中該處理係在鹵化溶劑中進行。 The method of claim 55, wherein the treating is carried out in a halogenated solvent. 如請求項59之方法，其中該鹵化溶劑為二氯甲烷。 The method of claim 59, wherein the halogenated solvent is dichloromethane. 如請求項55之方法，其中該有機鹼包含三(C1-6 )烷基胺。The method of claim 55, wherein the organic base comprises a tri(C 1-6 )alkylamine. 如請求項55之方法，其中該有機鹼為三乙胺。 The method of claim 55, wherein the organic base is triethylamine. 如請求項55之方法，其中該式F12化合物係由還原式F11化合物： 或其鹽獲得。The method of claim 55, wherein the compound of formula F12 is a compound of formula F11: Or its salt is obtained. 如請求項63之方法，其中該還原係在碘化鈉、氯三甲基矽烷及甲醇存在下進行。 The method of claim 63, wherein the reduction is carried out in the presence of sodium iodide, chlorotrimethylnonane and methanol. 如請求項63之方法，其進一步包含如下純化該式F12化合物：a)使該式F12化合物與胺基保護劑反應以產生式F12'化合物： 或其鹽，其中Pg2 N為經保護之胺；b)純化該式F12'化合物以產生經純化之式F12'化合物；及c)使該經純化之式F12'化合物與胺基去保護劑反應以產生經純化之式F12化合物。The method of claim 63, further comprising purifying the compound of formula F12 by: a) reacting the compound of formula F12 with an amine protecting agent to produce a compound of formula F12': Or a salt thereof, wherein Pg 2 N is a protected amine; b) purifying the compound of formula F12' to produce a purified compound of formula F12'; and c) rendering the purified compound of formula F12' with an amine deprotecting agent The reaction is carried out to yield a purified compound of formula F12. 如請求項65之方法，其中該胺基保護劑為二碳酸二第三丁酯。 The method of claim 65, wherein the amine protecting agent is ditributyl dicarbonate. 如請求項65之方法，其中該純化係由矽膠層析法進行。 The method of claim 65, wherein the purifying is carried out by gelatin chromatography. 如請求項66之方法，其中該胺基去保護劑為鹽酸。 The method of claim 66, wherein the amine deprotecting agent is hydrochloric acid. 如請求項68之方法，其中該反應係在包含二烷之溶劑中進行。The method of claim 68, wherein the reaction system comprises It is carried out in a solvent of an alkane. 如請求項68或69之方法，其中該反應係在異丙醇中進行。 The method of claim 68 or 69, wherein the reaction is carried out in isopropanol. 如請求項63之方法，其中該式F11化合物如下獲得：以疊氮化物試劑處理式F10化合物： 或其鹽，其中L1 係選自C1-4 烷基磺醯基、C1-4 鹵烷基磺醯基及芳基磺醯基；以產生該式F11化合物。The method of claim 63, wherein the compound of formula F11 is obtained by treating a compound of formula F10 with an azide reagent: Or a salt thereof, wherein L 1 is selected from the group consisting of C 1-4 alkylsulfonyl, C 1-4 haloalkylsulfonyl and arylsulfonyl; to produce the compound of formula F11. 如請求項71之方法，其中L1 為C1-4 烷基磺醯基。The method of claim 71, wherein L 1 is C 1-4 alkylsulfonyl. 如請求項72之方法，其中該烷基磺醯基為甲烷磺醯基。 The method of claim 72, wherein the alkylsulfonyl group is a methanesulfonyl group. 如請求項71之方法，其中該疊氮化物試劑為疊氮化鈉。 The method of claim 71, wherein the azide reagent is sodium azide. 如請求項55之方法，其中該式F12化合物如下獲得：使式F24化合物： 或其鹽，其中Pg3 N為經保護之胺；與胺基去保護劑反應以產生該式F12化合物。The method of claim 55, wherein the compound of formula F12 is obtained by: making a compound of formula F24: Or a salt thereof, wherein Pg 3 N is a protected amine; reacting with an amine deprotecting agent to produce the compound of formula F12. 如請求項75之方法，其中該經保護之胺為(C6 H5 )3 C-NH。The method of claim 75, wherein the protected amine is (C 6 H 5 ) 3 C-NH. 如請求項75之方法，其中該經保護之胺為(C6 H5 )2 C=N。The method of claim 75, wherein the protected amine is (C 6 H 5 ) 2 C=N. 如請求項75至77中任一項之方法，其中該去保護劑包含有機酸。 The method of any one of clauses 75 to 77, wherein the deprotecting agent comprises an organic acid. 如請求項75至76中任一項之方法，其中該去保護劑包含有機酸及有機矽烷。 The method of any one of claims 75 to 76, wherein the deprotecting agent comprises an organic acid and an organic decane. 如請求項79之方法，其中該有機酸為三氟乙酸及該有機矽烷包含三烷基矽烷。 The method of claim 79, wherein the organic acid is trifluoroacetic acid and the organodecane comprises a trialkylnonane. 如請求項80之方法，其中該三烷基矽烷為三(異丙基)矽烷。 The method of claim 80, wherein the trialkylnonane is tris(isopropyl)decane. 如請求項78之方法，其中該有機酸為三氟乙酸。 The method of claim 78, wherein the organic acid is trifluoroacetic acid. 如請求項75之方法，其中該式F24化合物如下獲得：式F22化合物： 或其鹽，以式F25化合物： 或其鹽，其中Pg3 N為經保護之胺；及偶合試劑處理，以產生該式F24化合物。The method of claim 75, wherein the compound of formula F24 is obtained as follows: a compound of formula F22: Or a salt thereof, a compound of the formula F25: Or a salt thereof, wherein Pg 3 N is a protected amine; and a coupling reagent to produce the compound of formula F24. 如請求項83之方法，其中該經保護之胺為(C6 H5 )3 C-NH。The method of claim 83, wherein the protected amine is (C 6 H 5 ) 3 C-NH. 如請求項83之方法，其中該經保護之胺為(C6 H5 )2 C=N。The method of claim 83, wherein the protected amine is (C 6 H 5 ) 2 C=N. 一種製備式F15化合物或其鹽之方法： 其中R2 為Cl、Br、CF3 、CH3 或CN；R3 為H或F；n為1或2，該方法包含：a)使式F12化合物： 或其鹽與磺醯胺及有機鹼反應以產生式F14化合物： 或其鹽，及b)使該式F14化合物或其鹽與鹼反應以產生該式F15化合物。A method for preparing a compound of the formula F15 or a salt thereof: Wherein R 2 is Cl, Br, CF 3 , CH 3 or CN; R 3 is H or F; n is 1 or 2, and the process comprises: a) bringing a compound of formula F12: Or a salt thereof is reacted with a sulfonamide and an organic base to produce a compound of formula F14: Or a salt thereof, and b) reacting the compound of the formula F14 or a salt thereof with a base to produce the compound of the formula F15. 如請求項86之方法，其中該有機鹼為吡啶。 The method of claim 86, wherein the organic base is pyridine. 如請求項86之方法，其中該式F12化合物反應進一步包含將反應物加熱。 The method of claim 86, wherein the reacting the compound of formula F12 further comprises heating the reactants. 如請求項88之方法，其中該加熱係使用微波照射進行。 The method of claim 88, wherein the heating is performed using microwave irradiation. 如請求項86之方法，其中該鹼包含鹼金屬氫氧化物。 The method of claim 86, wherein the base comprises an alkali metal hydroxide. 如請求項86之方法，其中該鹼為氫氧化鈉。 The method of claim 86, wherein the base is sodium hydroxide. 一種式F14化合物： 或其鹽，其中R2 為Cl、Br、CF3 、CH3 或CN；R3 為H或F；n為1或2。A compound of formula F14: Or a salt thereof, wherein R 2 is Cl, Br, CF 3 , CH 3 or CN; R 3 is H or F; n is 1 or 2. 如請求項92之化合物，其中R2 為Br，R3 為F，n為1。The compound of claim 92, wherein R 2 is Br, R 3 is F, and n is 1. 如請求項92之化合物，其中R2 為Br，R3 為F，n為2。The compound of claim 92, wherein R 2 is Br, R 3 is F, and n is 2. 如請求項92之化合物，其中R2 為Cl，R3 為F，n為1。The compound of claim 92, wherein R 2 is Cl, R 3 is F, and n is 1. 如請求項92之化合物，其中R2 為Cl，R3 為F，n為2。The compound of claim 92, wherein R 2 is Cl, R 3 is F, and n is 2. 如請求項92之化合物，其中R2 為CF3 ，R3 為F，n為1。The compound of claim 92, wherein R 2 is CF 3 , R 3 is F, and n is 1. 如請求項92之化合物，其中R2 為CF3 ，R3 為F，n為2。The compound of claim 92, wherein R 2 is CF 3 , R 3 is F, and n is 2. 如請求項92之化合物，其中R2 為CF3 ，R3 為H，n為1。The compound of claim 92, wherein R 2 is CF 3 , R 3 is H, and n is 1. 如請求項92之化合物，其中R2 為CF3 ，R3 為H，n為2。The compound of claim 92, wherein R 2 is CF 3 , R 3 is H, and n is 2. 如請求項92之化合物，其中R2 為CH3 ，R3 為F，n為1。The compound of claim 92, wherein R 2 is CH 3 , R 3 is F, and n is 1. 如請求項92之化合物，其中R2 為CN，R3 為F，n為1。The compound of claim 92, wherein R 2 is CN, R 3 is F, and n is 1. 一種製備式F19化合物或其鹽之方法： 其中R2 為Cl、Br、CF3 、CH3 或CN；R3 為H或F；n為1或2；該方法包含：a)使式F12化合物： 或其鹽與甲烷磺醯氯在有機鹼存在下反應以產生式F20化合物： b)使該式F20化合物或其鹽與鹼反應以產生該式F19化合物。A method for preparing a compound of the formula F19 or a salt thereof: Wherein R 2 is Cl, Br, CF 3 , CH 3 or CN; R 3 is H or F; n is 1 or 2; the process comprises: a) bringing a compound of formula F12: Or a salt thereof and methanesulfonium chloride are reacted in the presence of an organic base to produce a compound of formula F20: b) reacting a compound of the formula F20 or a salt thereof with a base to produce the compound of the formula F19. 如請求項103之方法，其中該式F12化合物反應進一步包含鹵化溶劑。 The method of claim 103, wherein the compound of formula F12 further comprises a halogenating solvent. 如請求項104之方法，其中該鹵化溶劑為二氯甲烷。 The method of claim 104, wherein the halogenated solvent is dichloromethane. 如請求項103之方法，其中該有機鹼包含三(C1-6 )烷基胺。The method of claim 103, wherein the organic base comprises a tri(C 1-6 )alkylamine. 如請求項103之方法，其中該有機鹼為三乙胺。 The method of claim 103, wherein the organic base is triethylamine. 如請求項103之方法，其中該鹼包含水性鹼。 The method of claim 103, wherein the base comprises an aqueous base. 如請求項103之方法，其中該鹼包含鹼金屬氫氧化物。 The method of claim 103, wherein the base comprises an alkali metal hydroxide. 如請求項103之方法，其中該鹼包含氫氧化鈉。 The method of claim 103, wherein the base comprises sodium hydroxide. 一種製備式F19化合物或其鹽之方法： 其中R2 為Cl、Br、CF3 、CH3 或CN；R3 為H或F；n為1或2；該方法包含：a)使式F17化合物： 或其鹽與鹽酸反應，隨後以亞硝酸鹽試劑處理，以產生式F18化合物： 或其鹽；及b)使該式F18化合物與式F27化合物： 或其鹽反應，以產生該式F19化合物。A method for preparing a compound of the formula F19 or a salt thereof: Wherein R 2 is Cl, Br, CF 3 , CH 3 or CN; R 3 is H or F; n is 1 or 2; the process comprises: a) bringing a compound of formula F17: Or a salt thereof is reacted with hydrochloric acid, followed by treatment with a nitrite reagent to produce a compound of formula F18: Or a salt thereof; and b) a compound of the formula F18 and a compound of the formula F27: Or a salt thereof is reacted to produce the compound of formula F19. 如請求項111之方法，其中R2 為Br，R3 為F，n為1。The method of claim 111, wherein R 2 is Br, R 3 is F, and n is 1. 如請求項111之方法，其中R2 為Br，R3 為F，n為2。The method of claim 111, wherein R 2 is Br, R 3 is F, and n is 2. 如請求項111之方法，其中R2 為Cl，R3 為F，n為1。The method of claim 111, wherein R 2 is Cl, R 3 is F, and n is 1. 如請求項111之方法，其中R2 為Cl，R3 為F，n為2。The method of claim 111, wherein R 2 is Cl, R 3 is F, and n is 2. 如請求項111之方法，其中R2 為CF3 ，R3 為F，n為1。The method of claim 111, wherein R 2 is CF 3 , R 3 is F, and n is 1. 如請求項111之方法，其中R2 為CF3 ，R3 為F，n為2。The method of claim 111, wherein R 2 is CF 3 , R 3 is F, and n is 2. 如請求項111之方法，其中R2 為CF3 ，R3 為H，n為1。The method of claim 111, wherein R 2 is CF 3 , R 3 is H, and n is 1. 如請求項111之方法，其中R2 為CF3 ，R3 為H，n為2。The method of claim 111, wherein R 2 is CF 3 , R 3 is H, and n is 2. 如請求項111之方法，其中R2 為CH3 ，R3 為F，n為1。The method of claim 111, wherein R 2 is CH 3 , R 3 is F, and n is 1. 如請求項111之方法，其中R2 為CN，R3 為F，n為1。The method of claim 111, wherein R 2 is CN, R 3 is F, and n is 1. 如請求項111之方法，其中該亞硝酸鹽試劑為亞硝酸鈉水溶液。 The method of claim 111, wherein the nitrite reagent is an aqueous solution of sodium nitrite. 一種式F18化合物： 或其鹽，其中n為1或2。A compound of formula F18: Or a salt thereof, wherein n is 1 or 2. 如請求項123之化合物，其中n為1。 A compound of claim 123, wherein n is one. 如請求項123之化合物，其中n為2。 A compound of claim 123, wherein n is 2. 一種製備式F28化合物或其鹽之方法： 其中R4 為F、Cl、Br或I；n為1或2；該方法包含：a)使式F29化合物： 或其鹽與磺醯胺及有機鹼反應以產生式F30化合物： 或其鹽，及b)使該式F30化合物與鹼反應以產生該式F28化合物。A method for preparing a compound of the formula F28 or a salt thereof: Wherein R 4 is F, Cl, Br or I; n is 1 or 2; the process comprises: a) bringing a compound of formula F29: Or a salt thereof is reacted with a sulfonamide and an organic base to produce a compound of formula F30: Or a salt thereof, and b) reacting the compound of formula F30 with a base to produce the compound of formula F28. 如請求項126之方法，其中R4 為Cl及n為1。The method of claim 126, wherein R 4 is Cl and n is 1. 如請求項126之方法，其中R4 為Br及n為1。The method of claim 126, wherein R 4 is Br and n is 1. 如請求項126之方法，其中該有機鹼包含吡啶。 The method of claim 126, wherein the organic base comprises pyridine. 如請求項126之方法，其中該式F29化合物反應進一步包含將反應物加熱。 The method of claim 126, wherein the reacting the compound of formula F29 further comprises heating the reactant. 如請求項130之方法，其中該加熱係使用微波照射進行。 The method of claim 130, wherein the heating is performed using microwave irradiation. 如請求項126之方法，其中該鹼包含水性鹼。 The method of claim 126, wherein the base comprises an aqueous base. 如請求項126之方法，其中該鹼包含鹼金屬氫氧化物。 The method of claim 126, wherein the base comprises an alkali metal hydroxide. 如請求項126之方法，其中該鹼包含氫氧化鈉。 The method of claim 126, wherein the base comprises sodium hydroxide. 如請求項126之方法，其中該式F29化合物係由還原式F31化合物： 或其鹽獲得。The method of claim 126, wherein the compound of formula F29 is a compound of formula F31: Or its salt is obtained. 如請求項135之方法，其中該還原係在碘化鈉、氯三甲基矽烷及甲醇存在下進行。 The method of claim 135, wherein the reduction is carried out in the presence of sodium iodide, chlorotrimethylnonane, and methanol. 如請求項135之方法，其中該式F31化合物如下獲得：以疊氮化物試劑處理式F32化合物： 或其鹽，其中L1 係選自C1-4 烷基磺醯基、C1-4 鹵烷基磺醯基及芳基磺醯基；以獲得該式F31化合物。The method of claim 135, wherein the compound of formula F31 is obtained by treating a compound of formula F32 with an azide reagent: Or a salt thereof, wherein L 1 is selected from the group consisting of C 1-4 alkylsulfonyl, C 1-4 haloalkylsulfonyl and arylsulfonyl; to obtain the compound of the formula F31. 如請求項137之方法，其中L1 為C1-4 烷基磺醯基。The method of claim 137, wherein L 1 is C 1-4 alkylsulfonyl. 如請求項138之方法，其中該烷基磺醯基包含甲烷磺醯基。 The method of claim 138, wherein the alkylsulfonyl group comprises a methanesulfonyl group. 如請求項137之方法，其中該疊氮化物試劑包含疊氮化鈉。 The method of claim 137, wherein the azide reagent comprises sodium azide.
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